N-methyl-n-(1-phenyl-2-(1-pyrrolidinyl)ethyl)-2-aminophenylacetamide derivatives agonists for the kappa opioid receptor

ABSTRACT

Compounds and pharmaceutically acceptable salts and solvates thereof are described. The compounds relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology and organic chemistry.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.15/539,061, filed Jun. 22, 2017, now allowed, which is a 35 U.S.C. § 371application of International Application NO. PCT/US2015/066725, filedDec. 18, 2015, designating the United States, which claims the benefitof priority to Indian Patent Application No. 3872/DEL/2014, filed Dec.23, 2014, the disclosures of which are incorporated herein by referencein their entireties.

BACKGROUND

The present disclosure relates to novel compounds and to their use asagonists of the kappa opioid receptor. The disclosure also relates tomethods for preparation of the compounds and to pharmaceuticalcompositions containing such compounds. The compounds described hereinrelate to and/or have application(s) in (among others) the fields ofdrug discovery, pharmacotherapy, physiology, organic chemistry andpolymer chemistry.

Kappa opioid agonists that exhibit full agonist properties at the kappaopioid receptor have been widely shown to be efficacious in preclinicalmodels of pain, particularly visceral pain. Kappa opioid agonists areunderstood to lack several of the side effects of mu opioid agonists,including abuse liability, gastrointestinal transit inhibition andrespiratory depression. Kappa opioid agonists, however, are understoodto produce complicating side effects, such as dysphoria and sedation atanalgesic doses. As a result, the presence of these side effects hashindered the development of kappa opioid agonists as clinically usefulanalgesics.

Beyond analgesia, kappa agonists have shown anti-inflammatory effectsboth in vitro and in vivo. Additionally, asimadoline, a kappa opioidagonist that is moderately restricted to the periphery, is currentlyundergoing studies for the treatment of irritable bowel syndrome. Due toits limited CNS entry, asimadoline may reduce the extent of side effectsassociated with less restricted kappa agonists, though studies are stillongoing. Additional known kappa opioid agonists, such as enadoline andspiradoline, enter the CNS (central nervous system) causing dysphoria,and thus have not been developed clinically or have been discontinueddue to CNS side effects. Further, while mixed agonists (acting on kappaand mu receptors) have been marketed, to date, no full kappa agonist hasbeen approved for use in humans.

The incorporation of a poly(ethylene glycol) moiety into a smallmolecule scaffold has been utilized to modify the rate of CNS entry ofseveral classes of molecules. U.S. Patent Application Publication No.2005/0136031 and U.S. Patent Application Publication No. 2010/0048602.The sites of incorporation and further modifications to the molecules,however, have differing effects on the overall activity andpharmacological properties of the resulting molecule.

In view of the above, there remains a need for peripherally acting kappaopioid agonists that retain sufficient efficacy to treat visceral painand other symptoms or disease states associated with the kappa opioidreceptor, while reducing the CNS side effects. The present inventionseeks to address these and other needs.

SUMMARY

In the compounds of the invention are structurally encompassed orrelated to one or more of the following five formulae:

Compounds falling within or related to these structures will bedescribed in further detail below.

In one or more embodiments of the invention, a composition is provided,the composition comprising (i) a compound as described herein, and,optionally, (ii) a pharmaceutically acceptable excipient.

In one or more embodiments of the invention, composition of matter isprovided, the composition of matter comprising a compound as describedherein, wherein the compound is present in a dosage form.

In one or more embodiments of the invention, a method is provided, themethod comprising administering a compound as described herein to apatient in need thereof.

Additional embodiments of the present compounds, compositions, methods,and the like will be apparent from the following description, examples,and claims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment of the present invention. Additional aspects and advantagesof the present invention are set forth in the following description andclaims.

DETAILED DESCRIPTION

As used in this specification, the singular forms “a,” “an,” and “the”include plural referents unless the context clearly dictates otherwise.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions describedbelow.

“Pharmacologically effective amount,” “physiologically effectiveamount,” and “therapeutically effective amount” are used interchangeablyherein to mean the amount of a compound of the present invention aloneor present in a composition that is needed to provide a threshold levelof the compound in the bloodstream or in the target tissue. The preciseamount will depend upon numerous factors, e.g., the particular activeagent, the components and physical characteristics of the composition,intended patient population, patient considerations, and the like, andcan readily be determined by one skilled in the art, based upon theinformation provided herein and available in the relevant literature.

The term “patient,” refers to a living organism suffering from or proneto a condition that can be prevented or treated by administration of acompound as described herein, and includes both humans and animals.

The compounds of the invention, if chiral, may be in a racemic mixture,or an optically active form, for example, a single optically activeenantiomer, or any combination or ratio of enantiomers (i.e., scalemicmixture). In addition, the compound may possess one or more geometricisomers. With respect to geometric isomers, a composition can comprise asingle geometric isomer or a mixture of two or more geometric isomers. Acompound for use in the present invention can be in its customary activeform, or may possess some degree of modification.

The compounds of the invention can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

The term “pharmaceutically acceptable salt” refers to non-toxic salts ofthe compounds of this invention. Pharmaceutically acceptable acidaddition salts may be prepared from inorganic and organic acids. Saltsderived from inorganic acids include hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like. Saltsderived from organic acids include acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, p-toluene-sulfonic acid, salicylic acid, and the like. Alsoincluded are salts with acidic amino acid such as aspartate andglutamate. Base addition salts include alkali metal salts such as sodiumsalt and potassium salt; alkaline earth metal salts such as magnesiumsalt and calcium salt; ammonium salt; organic basic salts such astrimethylamine salt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt, and N,N′-dibenzylethylenediamine salt; and saltswith basic amino acid such as lysine salt and arginine salt. The saltsmay be in some cases hydrates or solvates.

The term “solvate” refers to a complex formed by the combining of acompound of the present invention and a solvent.

The term “hydrate” refers to the complex formed by the combining of acompound of the present invention and water.

Selected substituents comprising the compounds of Formula I may bepresent to a recursive degree. In this context, “recursive substituent”means that a substituent may recite another instance of itself. Themultiple recitations may be direct or indirect through a sequence ofother substituents. Because of the recursive nature of suchsubstituents, theoretically, a large number of compounds may be presentin any given embodiment. One of ordinary skill in the art of medicinalchemistry understands that the total number of such substituents isreasonably limited by the desired properties of the compound intended.Such properties include, by way of example and not limitation, physicalproperties such as molecular weight, solubility or log P, applicationproperties such as activity against the intended target, and practicalproperties such as ease of synthesis. Recursive substituents may be anintended aspect of the invention. One of ordinary skill in the art ofmedicinal chemistry understands the versatility of such substituents. Tothe degree that recursive substituents are present in an embodiment ofthe invention, they may recite another instance of themselves, 0, 1, 2,3, or 4 times.

Names of compounds of the present disclosure are provided using ACD/Namesoftware for naming chemical compounds (Advanced Chemistry Development,Inc., Toronto, Canada). Other compounds or radicals may be named withcommon names or systematic or non-systematic names. In some instances asubstituent for a given variable (e.g., R³) within of a generic formulais shown with a dash (“-”) as in “—CH₃” or with a squiggly line (e.g.,“˜”) as in “˜R¹;” each are used interchangeably herein. The naming andnumbering of the compounds of the disclosure is illustrated with arepresentative compound of the formula

which is named 2-(3,4-dichlorophenyl)-N-{(1S)-2-[(3S)-3-(2-methoxyethoxy)pyrrolidin-1-yl]-1-phenylethyl}-N-methylacetamide.

In certain embodiments, a compound is provided, the compound having astructure encompassed by the following formula:

wherein R¹ is selected from the group consisting of:

˜N(CH₃)CH₂CH₂OCH₃; ˜CH₂CH(CH₃)OH; ˜N(CH₂CH₂OCH₃)₂; and

and pharmaceutically acceptable salts and solvates of each of theforegoing.

In certain embodiments, a compound is provided, the compound having astructure encompassed by the following formula:

wherein R² is selected from the group consisting of: ˜CH₂OCH₂CF₃; and˜CH(CH₃)OH, and pharmaceutically acceptable salts and solvates of eachof the foregoing.

In certain embodiments, a compound is provided, the compound having astructure encompassed by the following formula:

wherein R³ is selected from the group consisting of:

and pharmaceutically acceptable salts and solvates of each of theforegoing.

In certain embodiments, a compound is provided, the compound having astructure encompassed by the following formula:

wherein:

G is selected from the group consisting of ˜C(O)˜ and ˜S(O)₂˜;

(a) is selected from 0, 1, 2, 3 and 4;

R⁴ is selected from the group consisting of:

and

J is ˜H or ˜CF₃,

and pharmaceutically acceptable salts and solvates of each of theforegoing, with the provisio that the compound is not

In certain embodiments, a compound is provided, the compound having astructure encompassed by the following formula:

wherein:

(b) is either 0 or 1; and

R⁵ is selected from the group consisting of:

˜NHCH₂CH₂OCH₂CH₂OCH₂CH₂OCF₃; ˜NHC(CH₃)₃; ˜NHCH₃; and ˜N(CH₃)₂;

and pharmaceutically acceptable salts and solvates of each of theforegoing.

In certain embodiments, a compound is provided, the compound beingselected from the group consisting of:

and pharmaceutically acceptable salts and solvates of each of theforegoing.

The compounds of the present invention may be prepared in accordancewith the approaches described in the examples section.

The compounds of the present invention are understood to have activityas agonists of the kappa opioid receptor. The ability of each compounddisclosed herein to act as kappa opioid agonists may be determined usingmethods known to those of skill in the art and as disclosed herein. Theactivity of compounds as kappa agonist can be assessed with in-vitrobinding and functional assays in kappa opioid receptor expressing celllines/membranes and compared to known kappa agonists.

Approaches for evaluating analgesic activity of a compound of thepresent invention in vivo include a “writhing test.” Briefly, thecompound to be tested is administered [by, for example, injection (e.g.,subcutaneous injection)] to the mouse. Thereafter, a 0.5% acetic acidsolution is administered (i.p.) to a mouse and the numbers of writhingresponses are counted for twenty minutes. Antinociception is quantifiedas reduction in the number of writhes respective to vehicle.

Beyond acting as kappa opioid agonists, the present compounds areintended to act primarily on kappa opioid receptors in the peripheralnervous system rather than those receptors in the central nervoussystem. The propensity of a compound of the present invention to crossthe blood-brain barrier may be measured by methods known to those ofskill in the art and those described herein.

With respect to the blood-brain barrier (“BBB”), this barrier consistsof a continuous layer of unique endothelial cells joined by tightjunctions. The cerebral capillaries, which comprise more than 95% of thetotal surface area of the BBB, represent the principal route for theentry of most solutes and drugs into the central nervous system.

As will be understood by one of skill in the art, molecular size,lipophilicity, and P-glycoprotein (“PgP”) interaction are among theprimary parameters affecting the intrinsic BBB permeability propertiesof a given molecule. That is to say, these factors, when taken incombination, play a significant role in determining whether a givenmolecule passes through the BBB. Other factors (e.g., other activetransport mechanisms) may also play a role in ultimately determiningwhether a given molecule will pass through the BBB.

With respect to molecular size, the molecular size plays a significantrole in determining whether a given molecule will pass through the BBB.Relatively very large molecules, for example a molecule having amolecular weight of 5,000 Daltons, will not cross the BBB, whereasrelatively small molecules are more likely to cross the BBB. Otherfactors, however, also play a role in BBB crossing. Antipyrine andatenolol are both small molecule drugs; antipyrine readily crosses theBBB, whereas passage of atenolol is very limited, or effectivelynon-existent. Antipyrine is an industry standard for a high BBBpermeation; atenolol is an industry standard for low permeation of theBBB. See, e.g., Summerfield et al., J Pharmacol Exp Ther 322:205-213(2007).

Lipophilicity is also a factor in BBB permeation. Lipophilicity may beexpressed as logP (partition coefficient) or in some instances logD(distribution coefficient). The logP (or logD) for a given molecule canbe readily assessed by one of skill in the art. The value for logP maybe a negative number (more hydrophilic molecules) or a positive number(more hydrophobic molecules). As used herein when referring to logP,“more negative” means moving in the direction, on the logP scale, frompositive to negative logP (e.g., a logP of 2.0 is “more negative” than alogP of 4.0, a logP of −2.0 is “more negative” than a logP of −1.0).Molecules having a negative logP (hydrophilic molecules) generally donot permeate the BBB.

Permeability across the BBB is also dependent on the influence oftransporters, such as P-glycoprotein, or PgP, an ATP-dependent effluxtransporter highly expressed at the BBB. One of skill in the art canreadily determine whether a compound is a substrate for PgP using invitro methods. Compounds which are substrates for PgP in vitro likelywill not permeate the BBB in vivo. Conversely, poor substrates for PgP,as assessed in vitro, are generally likely to display in vivopermeability of the BBB, provided the compound meets other criteria asdiscussed herein and as known to one of skill in the art. See, e.g.,Tsuji, NeuroRx 2:54-62 (2005) and Rubin and Staddon, Annu. Rev.Neurosci. 22:11-28 (1999).

Even in the context of multiple variables (e.g., molecular size,lipophilicity, transporter influences, linkage type), it is possible toanazlyze a particular compounds ability to cross the BBB using methodsknown to those of skill in the art.

For any given compound whose degree of BBB crossing ability is notreadily known, such BBB crossing ability can be determined using asuitable animal model such as an in situ rat brain perfusion (“RBP”)model. Briefly, the RBP technique involves cannulation of the carotidartery followed by perfusion with a compound solution under controlledconditions, followed by a wash out phase to remove compound remaining inthe vascular space. More specifically, in the RBP model, a cannula isplaced in the left carotid artery and the side branches are tied off. Aphysiologic buffer containing the analyte (typically but not necessarilyat a 5 micromolar concentration level) is perfused at a flow rate ofabout 10 mL/minute in a single pass perfusion experiment. After 30seconds, the perfusion is stopped and the brain vascular contents arewashed out with compound-free buffer for an additional 30 seconds. Thebrain tissue is then removed and analyzed for compound concentrationsvia liquid chromatograph with tandem mass spectrometry detection(LC/MS/MS). Alternatively, blood-brain barrier permeability can beestimated based upon a calculation of the compound's molecular polarsurface area (“PSA”), which is defined as the sum of surfacecontributions of polar atoms (usually oxygens, nitrogens and attachedhydrogens) in a molecule. The PSA has been shown to correlate withcompound transport properties such as blood-brain barrier transport.Methods for determining a compound's PSA can be found, e.g., in, Ertl etal. (2000) J. Med. Chem. 43:3714-3717 and Kelder et al. (1999) Pharm.Res. 16:1514-1519.

The compounds of the present invention are expected to have varyingdegrees of activity against the kappa agonist receptor as well asvarying degrees to which they cross the BBB. While the compounds of thepresent invention have activity against the kappa opioid receptor, theyare believed to also have some degree of exclusion from the centralnervous system.

Brain PK studies may also be conducted to measure the extent of brainentry in-vivo drug concentrations at enter the CNS at various timepost-dose. In brief, rodents are administered with the test article(oral, subcutaneous, or other). At various times post dose terminalblood is collected. Then the rodent is transcardially perfused with coldisotonic saline to remove as much blood from the tissues and brain areextracted. Both plasma and brain are measured for drug content withLC/MS/MS.

The locomotor activity (LMA) model may be conducted to measure changesin activity following test article administration, which may be used toassess the CNS effects of the drug. In brief, at a predetermined timepost-dose, rats are placed into observation chambers which are equippedwith infrared photocells that can sense motion in the x, y, and zplanes. Activity is measured as the number of photobeam breaks in agiven plane (horizontal or vertical) or total distance traveled.

In further embodiments, the invention provides for compositionscomprising the compounds disclosed herein and a pharmaceuticallyacceptable excipient or carrier. Generally, the compound itself will bein a solid form (e.g., a precipitate), which can be combined with asuitable pharmaceutical excipient that can be in either solid or liquidform.

Exemplary excipients include, without limitation, those selected fromthe group consisting of carbohydrates, inorganic salts, antimicrobialagents, antioxidants, surfactants, buffers, acids, bases, andcombinations thereof.

A carbohydrate such as a sugar, a derivatized sugar such as an alditol,aldonic acid, an esterified sugar, and/or a sugar polymer may be presentas an excipient. Specific carbohydrate excipients include, for example:monosaccharides, such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol,sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

The excipient can also include an inorganic salt or buffer such ascitric acid, sodium chloride, potassium chloride, sodium sulfate,potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic,and combinations thereof.

The preparation may also include an antimicrobial agent for preventingor deterring microbial growth. Nonlimiting examples of antimicrobialagents suitable for the present invention include benzalkonium chloride,benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate,thimersol, and combinations thereof.

An antioxidant can be present in the preparation as well. Antioxidantsare used to prevent oxidation, thereby preventing the deterioration ofthe compound or other components of the preparation. Suitableantioxidants for use in the present invention include, for example,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorous acid, monothioglycerol, propyl gallate, sodiumbisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, andcombinations thereof.

A surfactant may be present as an excipient. Exemplary surfactantsinclude: polysorbates, such as “Tween 20” and “Tween 80,” and pluronicssuch as F68 and F88 (both of which are available from BASF, Mount Olive,N.J.); sorbitan esters; lipids, such as phospholipids such as lecithinand other phosphatidylcholines, phosphatidylethanolamines (althoughpreferably not in liposomal form), fatty acids and fatty esters;steroids, such as cholesterol; and chelating agents, such as EDTA, zincand other such suitable cations.

Pharmaceutically acceptable acids or bases may be present as anexcipient in the preparation. Nonlimiting examples of acids that can beused include those acids selected from the group consisting ofhydrochloric acid, acetic acid, phosphoric acid, citric acid, malicacid, lactic acid, formic acid, trichloroacetic acid, nitric acid,perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, andcombinations thereof. Examples of suitable bases include, withoutlimitation, bases selected from the group consisting of sodiumhydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide,ammonium acetate, potassium acetate, sodium phosphate, potassiumphosphate, sodium citrate, sodium formate, sodium sulfate, potassiumsulfate, potassium fumerate, and combinations thereof.

The amount of the compound in the composition will vary depending on anumber of factors, but will optimally be a therapeutically effectivedose when the composition is stored in a unit dose container. Atherapeutically effective dose can be determined experimentally byrepeated administration of increasing amounts of the compound in orderto determine which amount produces a clinically desired endpoint.

The amount of any individual excipient in the composition will varydepending on the activity of the excipient and particular needs of thecomposition. Typically, the optimal amount of any individual excipientis determined through routine experimentation, i.e., by preparingcompositions containing varying amounts of the excipient (ranging fromlow to high), examining the stability and other parameters, and thendetermining the range at which optimal performance is attained with nosignificant adverse effects.

Generally, however, the excipient will be present in the composition inan amount of about 1% to about 99% by weight, in certain embodimentsfrom about 5%-98% by weight, in certain embodiments from about 15-95% byweight of the excipient, and in certain embodiments concentrations lessthan 30% by weight.

These foregoing pharmaceutical excipients along with other excipientsand general teachings regarding pharmaceutical compositions aredescribed in “Remington: The Science & Practice of Pharmacy”, 19^(th)ed., Williams & Williams, (1995), the “Physician's Desk Reference”,52^(nd) ed., Medical Economics, Montvale, N.J. (1998), and Kibbe, A. H.,Handbook of Pharmaceutical Excipients, 3^(rd) Edition, AmericanPharmaceutical Association, Washington, D.C., 2000.

The pharmaceutical compositions can take any number of forms and theinvention is not limited in this regard. In certain embodiments,preparations are in a form suitable for oral administration such as atablet, caplet, capsule, gel cap, troche, dispersion, suspension,solution, elixir, syrup, lozenge, transdermal patch, spray, suppository,and powder. Oral dosage forms are preferred for those compounds that areorally active, and include tablets, caplets, capsules, gel caps,suspensions, solutions, elixirs, and syrups, and can also comprise aplurality of granules, beads, powders or pellets that are optionallyencapsulated. Such dosage forms are prepared using conventional methodsknown to those in the field of pharmaceutical formulation and describedin the pertinent texts.

Tablets and caplets, for example, can be manufactured using standardtablet processing procedures and equipment. Direct compression andgranulation techniques are preferred when preparing tablets or capletscontaining the compounds described herein. In addition to the compound,the tablets and caplets will generally contain inactive,pharmaceutically acceptable carrier materials such as binders,lubricants, disintegrants, fillers, stabilizers, surfactants, coloringagents, and the like. Binders are used to impart cohesive qualities to atablet, and thus ensure that the tablet remains intact. Suitable bindermaterials include, but are not limited to, starch (including corn starchand pregelatinized starch), gelatin, sugars (including sucrose, glucose,dextrose and lactose), polyethylene glycol, waxes, and natural andsynthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone,cellulosic polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, microcrystalline cellulose, ethylcellulose, hydroxyethyl cellulose, and the like), and Veegum. Lubricantsare used to facilitate tablet manufacture, promoting powder flow andpreventing particle capping (i.e., particle breakage) when pressure isrelieved. Useful lubricants are magnesium stearate, calcium stearate,and stearic acid. Disintegrants are used to facilitate disintegration ofthe tablet, and are generally starches, clays, celluloses, algins, gums,or crosslinked polymers. Fillers include, for example, materials such assilicon dioxide, titanium dioxide, alumina, talc, kaolin, powderedcellulose, and microcrystalline cellulose, as well as soluble materialssuch as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, andsorbitol. Stabilizers, as well known in the art, are used to inhibit orretard drug decomposition reactions that include, by way of example,oxidative reactions.

Capsules are also preferred oral dosage forms, in which case thecompound-containing composition can be encapsulated in the form of aliquid or gel (e.g., in the case of a gel cap) or solid (includingparticulates such as granules, beads, powders or pellets). Suitablecapsules include hard and soft capsules, and are generally made ofgelatin, starch, or a cellulosic material. Two-piece hard gelatincapsules are preferably sealed, such as with gelatin bands or the like.

Included are parenteral formulations in the substantially dry form(typically as a lyophilizate or precipitate, which can be in the form ofa powder or cake), as well as formulations prepared for injection, whichare typically liquid and requires the step of reconstituting the dryform of parenteral formulation. Examples of suitable diluents forreconstituting solid compositions prior to injection includebacteriostatic water for injection, dextrose 5% in water,phosphate-buffered saline, Ringer's solution, saline, sterile water,deionized water, and combinations thereof.

In some cases, compositions intended for parenteral administration cantake the form of nonaqueous solutions, suspensions, or emulsions, eachtypically being sterile. Examples of nonaqueous solvents or vehicles arepropylene glycol, polyethylene glycol, vegetable oils, such as olive oiland corn oil, gelatin, and injectable organic esters such as ethyloleate.

The parenteral formulations described herein can also contain adjuvantssuch as preserving, wetting, emulsifying, and dispersing agents. Theformulations are rendered sterile by incorporation of a sterilizingagent, filtration through a bacteria-retaining filter, irradiation, orheat.

The compound can also be administered through the skin usingconventional transdermal patch or other transdermal delivery system,wherein the compound is contained within a laminated structure thatserves as a drug delivery device to be affixed to the skin. In such astructure, the compound is contained in a layer, or “reservoir,”underlying an upper backing layer. The laminated structure can contain asingle reservoir, or it can contain multiple reservoirs.

The compound can also be formulated into a suppository for rectaladministration. With respect to suppositories, the compound is mixedwith a suppository base material which is (e.g., an excipient thatremains solid at room temperature but softens, melts or dissolves atbody temperature) such as coca butter (theobroma oil), polyethyleneglycols, glycerinated gelatin, fatty acids, and combinations thereof.Suppositories can be prepared by, for example, performing the followingsteps (not necessarily in the order presented): melting the suppositorybase material to form a melt; incorporating the compound (either beforeor after melting of the suppository base material); pouring the meltinto a mold; cooling the melt (e.g., placing the melt-containing mold ina room temperature environment) to thereby form suppositories; andremoving the suppositories from the mold.

The invention also provides a method for administering a compoundprovided herein to a patient suffering from a condition that isresponsive to treatment with the compound such as pain. The methodcomprises administering, generally orally, a therapeutically effectiveamount of the compound (in certain embodiments provided as part of apharmaceutical preparation). Other modes of administration are alsocontemplated, such as pulmonary, nasal, buccal, rectal, sublingual,transdermal, and parenteral. As used herein, the term “parenteral”includes subcutaneous, intravenous, intra-arterial, intraperitoneal,intracardiac, intrathecal, and intramuscular injection, as well asinfusion injections.

The method of administering may be used to treat any condition that canbe remedied or prevented by administration of a kappa opioid agonist.Most commonly, the compounds provided herein are administered for themanagement of pain, including visceral pain, chronic pelvic pain andinterstitial cystitis. Kappa agonists have also been used to treatirritable bowel syndrome. Those of ordinary skill in the art appreciatewhich conditions a specific compound can effectively treat. The actualdose to be administered will vary depend upon the age, weight, andgeneral condition of the subject as well as the severity of thecondition being treated, the judgment of the health care professional,and compound being administered. Therapeutically effective amounts areknown to those skilled in the art and/or are described in the pertinentreference texts and literature. Generally, a therapeutically effectiveamount will range from about 0.001 mg to 1000 mg, in certain embodimentsin doses from 0.01 mg/day to 750 mg/day, and in certain embodiments indoses from 0.10 mg/day to 500 mg/day.

The unit dosage of any given compound (in certain embodiments, providedas part of a pharmaceutical preparation) can be administered in avariety of dosing schedules depending on the judgment of the clinician,needs of the patient, and so forth. The specific dosing schedule will beknown by those of ordinary skill in the art or can be determinedexperimentally using routine methods. Exemplary dosing schedulesinclude, without limitation, administration five times a day, four timesa day, three times a day, twice daily, once daily, three times weekly,twice weekly, once weekly, twice monthly, once monthly, and anycombination thereof. Once the clinical endpoint has been achieved,dosing of the composition is halted.

All articles, books, patents, patent publications and other publicationsreferenced herein are hereby incorporated by reference in theirentireties.

It is to be understood that while the invention has been described inconjunction with certain and specific embodiments, the foregoingdescription as well as the examples that follow are intended toillustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

EXAMPLES

Unless otherwise indicated, all chemical reagents referred to in theappended examples are commercially available and/or can be synthesizedin accordance with methods described in the literature unless otherwiseindicated.

Example 1 Preparation of(S)—N-(1-(3-(4-cyano-3-(trifluoromethyl)phenylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide,hydrochloride salt

(S)—N-(1-(3-(4-cyano-3-(trifluoromethyl)phenylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamidemay be prepared according to the following steps.

Step 1: Preparation of2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(pyrrolidin-1-yl)ethyl]acetamide

(S)-1-[2-(Methylamino)-2-(3/4-nitrophenyl)ethyl]pyrroldin (0.66 g, 2.65mmol) [Portoghese (1994) Journal of Medicinal Chemistry 37:4490-4498]was dissolved in anhydrous acetonitrile (14 mL). To the dark solutionwas added diisopropylethylamine (1.03 mL, 5.82 mmol) at 0° C., followedby 3,4-dichlorophenylacetic acid (0.60 g, 2.91 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.96 g, 2.91 mmol). The reaction mixture was allowed to equilibrate toroom temperature. After approximately 17 hours at room temperature thereaction mixture was concentrated under reduced pressure. The residuewas taken up in ethyl acetate (15 mL) and washed with saturated sodiumbicarbonate (2×25 mL) and saturated sodium chloride (25 mL). Thecombined organic portion was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Purification by chromatography gave2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(pyrrolidin-1-yl)ethylacetamide (0.99 g, 86% yield), as a light-yellow oil. The compound wasconverted into the hydrochloride salt by dissolving the oil inacetonitrle and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as a white powder. ¹H NMR(500 MHz, CDCl₃): δ 8.13 (m, 2H), 7.66 (m, 1H), 7.51 (m, 1H), 7.37 (m,2H), 7.15 (m, 1H), 6.11 (m, 1H), 3.77 (m, 2H), 3.13 (m, 1H), 2.80 (m,1H), 2.69 (s, 3H), 2.60 (m, 2H), 1.76 (m, 4H); MS (EI) forC₂₁H₂₃C₁₂N₃O₃: 437 (MH⁺).

Step 2: Preparation ofN-[(1S)-1-(3-aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide

2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(pyrrolidin-1-yl)ethylacetamide (0.80 g, 1.77 mmol), hydrazine hydrate (1.36 g, 21.34 mmol)and Raney nickel slurry (1.0 mL) in 95% ethanol (89 mL) was heated to55° C. After approximately two hours the reaction was complete asindicated by TLC. The reaction mixture was filtered through Celite, andthe Raney nickel was washed with hot methanol. The combined filtrateswere concentrated under reduced pressure to give 0.60 g (83%) ofN-[(1S)-1-(3-aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide.¹H NMR (500 MHz, CDCl₃): δ 7.38 (m, 2H), 7.17 (m, 1H), 7.10 (m, 1H),6.63 (m, 3H), 6.01 (m, 1H), 3.66-3.79 (m, 4H), 3.14 (m, 1H), 2.46-2.72(m, 5H), 2.47 (m, 3H), 1.74 (m, 4H); MS (EI) for C₂₁H₂₅C₁₂N₃O: 406(MH⁺).

Step 3:(S)—N-(1-(3-(4-cyano-3-(trifluoromethyl)phenylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(2) (0.12 g, 0.30 mmol) was dissolved in dichloromethane (6 mL) andanhydrous pyridine (0.18 mL, 2.27 mmol). To the cooled (0° C.) yellowsolution there was added dropwise4-cyano-3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.21 g, 0.75mmol) in dichloromethane (1 mL). The yellow reaction mixture was stirredat 0° C., and the color turned orange. The reaction mixture was allowedto equilibrate to room temperature. After approximately 17 hours at roomtemperature, the reaction mixture was diluted with dichloromethane (25mL) and followed by the addition of water (30 mL). The aqueous portionwas extracted with dichloromethane (2×15 mL). In five separate washingsteps, the combined organic portions were washed in the followingsequence: a 1N hydrochloric acid wash, a water wash, a saturated sodiumbicarbonate wash, a second water wash and a brine wash (35 mL each). Theorganic portion was dried over anhydrous sodium sulfate, filtered,concentrated and purified by chromatography to give 0.08 g (41%)(S)—N-(1-(3-(4-cyano-3-(trifluoromethyl)phenylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 6.89-8.09 (m, 10H), 5.89 (m,1H), 3.59-3.75 (m, 2H), 3.12 (m, 1H), 2.68 (m, 4H), 2.50 (m, 2H), 1.14(m, 3H); MS (EI) for C₂₉H₂₇C₁₂F₃N₄O₃S: 639 (MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 2 Preparation of(S)-2-(3,4-dichlorophenyl)-N-(1-(3-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.13 g, 0.27 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (4.5 mL) and anhydrous pyridine (0.16 mL,2.06 mmol). To the cooled (0° C.) yellow solution there was addeddropwise 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonylchloride (0.17 g, 0.68 mmol) in dichloromethane (1 mL). The yellowreaction mixture was allowed to stir at 0° C., and the color turningorange. The reaction mixture was allowed to equilibrate to roomtemperature. After approximately 17 hours at room temperature, thereaction mixture was diluted with dichloromethane (25 mL) followed bythe addition of waster (30 mL). The aqueous portion was extracted withdichloromethane (2×15 mL). In five separate washing steps, the combinedorganic portions were washed in the following sequence: a 1Nhydrochloric acid wash, a water wash, a saturated sodium bicarbonatewash, a second water wash and a brine wash (35 mL each). The organicportion was dried over anhydrous sodium sulfate, filtered, concentratedand purified by chromatography to give 0.085 g (51%)(S)-2-(3,4-dichlorophenyl)-N-(1-(3-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 6.90-7.29 (m, 7H), 5.86 (m,1H), 3.69 (m, 3H), 3.39 (m, 4H), 3.28 (m, 4H), 3.05 (m, 1H), 2.68 (m,4H), 2.44 (m, 3H), 1.71 (m, 4H); MS (EI) for C₂₇H₃₁C₁₂N₅O₅S: 608 (MH⁺).The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 3 Preparation of(S)—N-(1-(3-(6-chloropyridine-3-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.11 g, 0.24 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (4 mL) and anhydrous pyridine (0.14 mL,1.80 mmol). To the cooled (0° C.) yellow solution there was addeddropwise 6-chloropyridine-3-sulfonyl chloride (0.13 g, 0.60 mmol) indichloromethane (1 mL). The yellow reaction mixture was allowed to stirat 0° C., and the color turned orange. The reaction mixture was allowedto equilibrate to room temperature. After approximately 17 hours at roomtemperature, the reaction mixture was diluted with dichloromethane (25mL) followed by the addition of water (30 mL). The aqueous portion wasextracted with dichloromethane (2×15 mL). In five separate washingsteps, the combined organic portions were washed in the followingsequence: a 1N hydrochloric acid wash, a water wash, a saturated sodiumbicarbonate wash, a second water wash and a brine wash (35 mL each). Theorganic portion was dried over anhydrous sodium sulfate, filtered,concentrated and purified by chromatography to give 0.085 g (61%)(S)—N-(1-(3-(6-chloropyridine-3-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamideas a yellow oil. MS (EI) for C₂₆H₂₇C₁₃N₄O₃S: 581(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 4 Preparation of(S)—N-(1-(3-(2-chloropyridine-3-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.11 g, 0.23 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (4 mL) and anhydrous pyridine (0.13 mL,1.72 mmol). To the cooled (0° C.) yellow solution there was addeddropwise 2-chloropyridine-3-sulfonyl chloride (0.12 g, 0.57 mmol) indichloromethane (1 mL). The yellow reaction mixture was allowed to stirat 0° C., and the color turned orange. The reaction mixture was allowedto equilibrate to room temperature. After approximately 17 hours at roomtemperature, the reaction mixture was diluted with dichloromethane (25mL) followed by the addition of water (30 mL). The aqueous portion wasextracted with dichloromethane (2×15 mL). In five separate washingsteps, the combined organic portions were washed in the followingsequence: a 1N hydrochloric acid wash, a water wash, a saturated sodiumbicarbonate wash, a second water wash and a brine wash (35 mL each). Theorganic portion was dried over anhydrous sodium sulfate, filtered,concentrated and purified by chromatography to give 0.072 g (54%)(S)—N-(1-(3-(2-chloropyridine-3-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.02-8.52 (m, 10H), 6.00 (m,1H), 3.74 (m, 2H), 2.67 (m, 5H), 2.48 (m, 2H), 1.77 (m, 6H); MS (EI) forC₂₆H₂₇C₃N₄O₃S: 581(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 5 Preparation of(S)-2-(3,4-dichlorophenyl)-N-methyl-N-(1-(3-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)acetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.11 g, 0.23 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (4 mL) and anhydrous pyridine (0.13 mL,1.72 mmol). To the cooled (0° C.) yellow solution there was addeddropwise 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride(0.15 g, 0.57 mmol) in dichloromethane (1 mL). The yellow reactionmixture was allowed to stir at 0° C., and the color turned orange. Thereaction mixture was allowed to equilibrate to room temperature. Afterapproximately 17 hours at room temperature, the reaction mixture wasdiluted with dichloromethane (25 mL) followed by the addition of water(30 mL). The aqueous portion was extracted with dichloromethane (2×15mL). In five separate washing steps, the combined organic portions werewashed in the following sequence: a 1N hydrochloric acid wash, a waterwash, a saturated sodium bicarbonate wash, a second water wash and abrine wash (35 mL each). The organic portion was dried over anhydroussodium sulfate, filtered, concentrated and purified by chromatography togive 0.10 g (70%)(S)-2-(3,4-dichlorophenyl)-N-methyl-N-(1-(3-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)acetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.05-7.92 (m, 8H), 5.97 (m,1H), 3.87 (s, 3H), 3.65 (m, 2H), 3.22 (m, 2H), 2.75 (m, 5H), 2.50 (m,2H), 1.78 (m, 3H); MS (EI) for C₂₆H₂₈C₁₂F₃N₅O₃S: 618(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 6 Preparation of(S)-2-(3,4-dichlorophenyl)-N-(1-(3-(3,5-dimethylisoxazole-4-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.11 g, 0.23 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (4 mL) and anhydrous pyridine (0.14 mL,1.72 mmol). To the cooled (0° C.) yellow solution there was addeddropwise 3,5-dimethylisoxazole-4-sulfonyl chloride (0.11 g, 0.57 mmol)in dichloromethane (1 mL). The yellow reaction mixture was allowed tostir at 0° C., and the color turned orange. The reaction mixture wasallowed to equilibrate to room temperature. After approximately 17 hoursat room temperature, the reaction mixture was diluted withdichloromethane (25 mL) followed by the addition of water (30 mL). Theaqueous portion was extracted with dichloromethane (2×15 mL). In fiveseparate washing steps, the combined organic portions were washed in thefollowing sequence: a 1N hydrochloric acid wash, a water wash, asaturated sodium bicarbonate wash, a second water wash and a brine wash(35 mL each). The organic portion was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by chromatography to give0.077 g (59%)(S)-2-(3,4-dichlorophenyl)-N-(1-(3-(3,5-dimethylisoxazole-4-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 6.93-7.30 (m, 7H), 5.92 (m,1H), 3.75 (m, 1H), 3.59 (m, 1H), 3.10 (m, 1H), 2.67 (m, 4H), 2.50 (m,1H), 2.39 (s, 3H), 2.17 (m, 3H), 1.73 (m, 4H); MS (EI) forC₂₆H₃₀C₁₂N₄O₄S: 565(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 7 Preparation of(S)-2-(3,4-dichlorophenyl)-N-(1-(3-((N-(2-methoxyethyl)-N-methylsulfamoyl)amino)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.12 g, 0.25 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dioxane (5 mL) and 1N sodium hydroxide (0.77 mL, 1.92mmol). To the cooled (0° C.) solution was added(2-methoxyethyl)(methyl)sulfamoyl chloride (0.12 g, 0.64 mmol), whilemaintaining the temperature less than 10° C. The yellow reaction mixturewas allowed to stir at 0° C., and the color turned orange. The reactionmixture was allowed to equilibrate to room temperature. Afterapproximately 17 hours at room temperature the reaction was diluted withdichloromethane followed by the addition of water. The aqueous portionwas extracted with dichloromethane (3×). The organic portion was washedwith water and saturated sodium chloride. The organic portion was driedover anhydrous sodium sulfate, filtered, concentrated and purified bychromatography to give 0.068 g (48%) of(S)-2-(3,4-dichlorophenyl)-N-(1-(3-((N-(2-methoxyethyl)-N-methylsulfamoyl)amino)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 6.95-7.30 (m, 7H), 6.01 (m,1H), 3.71 (m, 1H), 3.61 (m, 1H), 3.47 (m, 3H), 3.41 (m, 3H), 3.31 (s,3H), 2.80 (m, 4H), 2.74 (m, 4H), 2.45 (m, 2H), 1, 73 (m, 5H); MS (EI)for C₂₅H₃₄C₁₂N₄O₄S: 557(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 8 Preparation of2-(3,4-dichlorophenyl)-N-((1S)-1-(3-(2-hydroxypropylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamide,hydrochloride salt

Step 1: Preparation ofN-((1S)-1-(3-(2-((tert-butyldimethylsilyl)oxy)propylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.05 g, 0.10 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (1 mL) and anhydrous pyridine (63 μL, 0.78mmol). To the cooled (0° C.) yellow solution there was added dropwise2-((tert-butyldimethylsilyl)oxy)propane-1-sulfonyl chloride (0.07 g,0.26 mmol) in dichloromethane (1 mL). The yellow reaction mixture wasallowed to stir at 0° C., and the color turned orange. The reactionmixture was allowed to equilibrate to room temperature. Afterapproximately 17 hours at room temperature, the reaction mixture wasdiluted with dichloromethane (25 mL) followed by the addition of water(30 mL). The aqueous portion was extracted with dichloromethane (2×15mL). In five separate washing steps, the combined organic portions werewashed in the following sequence: a 1N hydrochloric acid wash, a waterwash, a saturated sodium bicarbonate wash, a second water wash and abrine wash (35 mL each). The organic portion was dried over anhydroussodium sulfate, filtered, concentrated and purified by chromatography togive 0.04 g (60%) ofN-((1S)-1-(3-(2-((tert-butyldimethylsilyl)oxy)propylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamideas a yellow oil. MS (EI) for C₃₀H₄₅C₁₂N₃O₄SSi: 642(MH⁺).

Step 2: Preparation of2-(3,4-dichlorophenyl)-N-((1S)-1-(3-(2-hydroxypropylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamide,hydrochloride salt

To a solution ofN-((1S)-1-(3-(2-((tert-butyldimethylsilyl)oxy)propylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(0.040 g, 0.059 mmol) in THF (5 mL) at 0° C. was addedtetra-N-butylammonium fluoride (0.17 mL, 0.17 mmol; 1 M intetrahydrofuran). After approximately 17 hours at room temperature thetetrahydrofuran was removed under reduced pressure. The residue waspurified by chromatography to give 0.024 g (77%) of2-(3,4-dichlorophenyl)-N-((1S)-1-(3-(2-hydroxypropylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 6.94-7.30 (m, 7H), 5.96 (m,1H), 4.32 (m, 1H), 3.75 (m, 1H), 3.62 (m, 1H), 2.98-3.25 (m, 3H), 2.80(m, 2H), 2.72 (m, 4H), 2.58 (m, 2H), 2.45 (m, 1H), 1.75 (m, 3H), 1.60(m, 1H), 1.34 (m, 1H), 1.15 (m, 3H); MS (EI) for C₂₄H₃₁C₁₂N₃O₄S:528(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 9 Preparation of(S)—N-(1-(3-((N,N-bis(2-methoxyethyl)sulfamoyl)amino)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.12 g, 0.25 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (4 mL) and anhydrous pyridine (0.15 mL,1.89 mmol). To the cooled (0° C.) yellow solution was added dropwisebis(2-methoxyethyl)sulfamoyl chloride (0.15 g, 0.63 mmol) indichloromethane (1 mL). The yellow reaction mixture was allowed to stirat 0° C., and the color turned orange. The reaction mixture was allowedto equilibrate to room temperature. After approximately 17 hours at roomtemperature, the reaction mixture was diluted with dichloromethane (25mL) followed by the addition of water (30 mL). The aqueous portion wasextracted with dichloromethane (2×15 mL). In five separate washingsteps, the combined organic portions were washed in the followingsequence: a 1N hydrochloric acid wash, a water wash, a saturated sodiumbicarbonate wash, a second water wash and a brine wash (35 mL each). Theorganic portion was dried over anhydrous sodium sulfate, filtered,concentrated and purified by chromatography to give 0.08 g (53%) of(S)—N-(1-(3-((N,N-bis(2-methoxyethyl)sulfamoyl)amino)phenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.05-7.38 (m, 7H), 6.10 (m,1H), 3.80 (m, 1H), 3.72 (m, 1H), 3.58 (m, 6H), 3.41 (m, 5H), 2.75 (m,2H), 2.52 (m, 1H), 1.77 (m, 2H), 1.61 (m, 12H); MS (EI) forC₂₇H₃₈C₁₂N₄O₅S: 601(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 10 Preparation of(S)-2-(3,4-dichlorophenyl)-N-(1-(3-(4,5-dichlorothiophene-2-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.12 g, 0.25 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (4 mL) and anhydrous pyridine (0.16 mL,1.98 mmol). To the cooled (0° C.) yellow solution there was addeddropwise 4,5-dichlorothiophene-2-sulfonyl chloride (0.17 g, 0.66 mmol)in dichloromethane (1 mL). The yellow reaction mixture was allowed tostir at 0° C., and the color turned orange. The reaction mixture wasallowed to equilibrate to room temperature. After approximately 17 hoursat room temperature, the reaction mixture was diluted withdichloromethane (25 mL) followed by the addition of water (30 mL). Theaqueous portion was extracted with dichloromethane (2×15 mL). In fiveseparate washing steps, the combined organic portions were washed in thefollowing sequence: a 1N hydrochloric acid wash, a water wash, asaturated sodium bicarbonate wash, a second water wash and a brine wash(35 mL each). The organic portion was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by chromatography to give0.10 g (60%) of(S)-2-(3,4-dichlorophenyl)-N-(1-(3-(4,5-dichlorothiophene-2-sulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methylacetamides a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 6.93-7.31 (m, 8H), 5.96 (m,1H), 3.62-3.70 (m, 3H), 3.12 (m, 1H), 2.71 (m, 3H), 2.63 (m, 3H), 2.51(m, 2H), 1.72 (m, 4H); MS (EI) for C₂₅H₂₅C₁₄N₃O₃S₂: 622(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 11 Preparation of(S)—N-methyl-2,2-diphenyl-N-(2-(pyrrolidin-1-yl)-1-(3-(2-(2,2,2-trifluoroethoxy)ethylsulfonamido)phenyl)ethyl)acetamide,hydrochloride salt

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.14 g, 0.35 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (6 mL) and anhydrous pyridine (0.21 mL,2.65 mmol). To the cooled (0° C.) yellow solution there was addeddropwise 2-(2,2,2-trifluoroethoxy)ethanesulfonyl chloride (0.21 g, 0.88mmol) in dichloromethane (1 mL). The yellow reaction mixture was allowedto stir at 0° C., and the color turned orange. The reaction mixture wasallowed to equilibrate to room temperature. After approximately 17 hoursat room temperature, the reaction mixture was diluted withdichloromethane (25 mL) followed by the addition of water (30 mL). Theaqueous portion was extracted with dichloromethane (2×15 mL). In fiveseparate washing steps, the combined organic portions were washed in thefollowing sequence: a 1N hydrochloric acid wash, a water wash, asaturated sodium bicarbonate wash, a second water wash and a brine wash(35 mL each). The organic portion was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by chromatography to give0.16 g (77%) of((S)—N-methyl-2,2-diphenyl-N-(2-(pyrrolidin-1-yl)-1-(3-(2-(2,2,2-trifluoroethoxy)ethylsulfonamido)phenyl)ethyl)acetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.12-7.30 (m, 14H), 6.21 (m,1H), 3.85-3.97 (m, 4H), 3.20 (m, 2H), 2.78 (m, 4H), 2.25 (m, 1H), 2.15(m, 1H), 1.95 (m, 2H), 1.54 (m, 7H); MS (EI) for C₃₁H₃₆F₃N₃O₄S:604(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 12 Preparation ofN-((1S)-1-(3-(2-hydroxypropylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2,2-diphenylacetamide,hydrochloride salt

Step 1: Preparation of(S)—N-methyl-N-(1-(3-nitrophenyl)-2-(pyrrolidin-1-yl)ethyl)-2,2-diphenylacetamide

(S)-1-[2-(Methylamino)-2-(3/4-nitrophenyl)ethyl]pyrroldin (0.31 g, 1.25mmol) [Portoghese (1994) Journal of Medicinal Chemistry 37:4490-4498]was dissolved in anhydrous dichloromethane (6 mL). The dark solution wasstirred at 0° C., under nitrogen, followed by the addition ofdiisopropylethylamine (0.44 mL, 2.52 mmol), and 2,2-diphenylacetylchloride (0.35 g, 1.38 mmol). The reaction mixture was allowed toequilibrate to room temperature. After approximately 17 hours at roomtemperature the mixture was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (8 mL) and was washed withsaturated sodium bicarbonate (2×15 mL) and saturated sodium chloride (15mL). The combined organic portion was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by chromatography to give 0.51 g (86%) of(S)—N-methyl-N-(1-(3-nitrophenyl)-2-(pyrrolidin-1-yl)ethyl)-2,2-diphenylacetamideas a yellow oil. MS (EI) for C₂₂H₂₄F₃N₃O₃: 436 (MH⁺).

Step 2: Preparation of(S)—N-(1-(3-aminophenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2,2-diphenylacetamide

A mixture of(S)—N-methyl-N-(1-(3-nitrophenyl)-2-(pyrrolidin-1-yl)ethyl)-2,2-diphenylacetamide(0.40 g, 0.90 mmol), hydrazine hydrate (0.69 g, 10.8 mmol) and Raneynickel slurry (2.0 mL) in 95% ethanol (45 mL) was heated to 55° C. Afterapproximately two hours at 55° C. the reaction was complete as indicatedby LC-MS. The reaction mixture was filtered through Celite, and theRaney nickel was washed with hot methanol. The filtrate was concentratedunder reduced pressure, and the residue was purified by chromatographyto give 0.21 g (44%) of(S)—N-(1-(3-aminophenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2,2-diphenylacetamideas a light-yellow oil. MS (EI) for C₂₇H₃₁N₃O: 414 (MH⁺).

Step 3: Preparation ofN-((1S)-1-(3-(2-((tert-butyldimethylsilyl)oxy)propylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2,2-diphenylacetamide

N-[(1S)-1-(3-Aminophenyl)-2-(pyrrolidin-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide(0.16 g, 0.38 mmol) (preparation described in Step 2 of Example 1) wasdissolved in dichloromethane (7 mL) and anhydrous pyridine (0.23 mL,2.90 mmol). To the cooled (0° C.) yellow solution there was addeddropwise 2-((tert-butyldimethylsilyl)oxy)propane-1-sulfonyl chloride(0.27 g, 0.96 mmol) in dichloromethane (1 mL). The yellow reactionmixture was allowed to stir at 0° C., and the color turned orange. Thereaction mixture was allowed to equilibrate to room temperature. Afterapproximately 17 hours at room temperature, the reaction mixture wasdiluted with dichloromethane (25 mL) followed by the addition of water(30 mL). The aqueous portion was extracted with dichloromethane (2×15mL). In five separate washing steps, the combined organic portions werewashed in the following sequence: a 1N hydrochloric acid wash, a waterwash, a saturated sodium bicarbonate wash, a second water wash and abrine wash (35 mL each). The organic portion was dried over anhydroussodium sulfate, filtered, concentrated and purified by chromatography togive 0.19 g (76%) ofN-((1S)-1-(3-(2-((tert-butyldimethylsilyl)oxy)propylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2,2-diphenylacetamideas a yellow oil. MS (EI) for C₃₆H₅₁N₃O₄SSi: 650(MH⁺).

Step 4: Preparation ofN-((1S)-1-(3-(2-hydroxypropylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2,2-diphenylacetamide,hydrochloride salt

To a solution ofN-((1S)-1-(3-(2-((tert-butyldimethylsilyl)oxy)propylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2,2-diphenylacetamide(0.19 g, 0.29 mmol) in THF (6 mL) at 0° C. was addedtetra-N-butylammonium fluoride (0.87 mL, 0.87 mmol; 1 M intetrahydrofuran). After approximately 17 hours at room temperature thetetrahydrofuran was removed under reduced pressure. The residue waspurified by chromatography to give 0.13 g (85%) ofN-((1S)-1-(3-(2-hydroxypropylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2,2-diphenylacetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.09-7.37 (m, 14H), 6.09 (m,1H), 4.37 (m, 1H), 3.07-3.23 (m, 5H), 2.63-2.90 (m, 6H), 2.45 (m, 2H),1.80 (m, 4H), 1.25 (m, 4H); MS (EI) for C₃₀H₃₇N₃O₄S: 536(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 13 Preparation ofN-((1S)-1-(3-(2-hydroxypropylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamide,hydrochloride salt

Step 1: Preparation of(S)—N-methyl-N-(1-(3-nitrophenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamide

(S)-1-[2-(Methylamino)-2-(3/4-nitrophenyl)ethyl]pyrroldin (0.34 g, 1.38mmol) [Portoghese (1994) Journal of Medicinal Chemistry 37:4490-4498]was dissolved in anhydrous acetonitrile (7 mL). The dark solution wasstirred at 0° C., under nitrogen, followed by the addition ofdiisopropylethylamine (0.54 mL, 3.04 mmol),2-(4-(trifluoromethyl)phenyl)acetic acid (0.31 g, 1.52 mmol), andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.50 g, 1.52 mmol). The reaction mixture was allowed to equilibrate toroom temperature. After approximately 17 hours at room temperature themixture was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (8 mL) and was washed with saturated sodiumbicarbonate (2×15 mL) and saturated sodium chloride (15 mL). Thecombined organic portion was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by chromatography to give 0.51 g (86%) of(S)—N-methyl-N-(1-(3-nitrophenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamideas a yellow oil. MS (EI) for C₂₂H₂₄F₃N₃O₃: 436 (MH⁺).

Step 2: Preparation of(S)—N-(1-(3-aminophenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamide

A mixture of(S)—N-methyl-N-(1-(3-nitrophenyl)-2-(pyrrolidin-1-yl)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamide(0.51 g, 1.18 mmol), hydrazine hydrate (0.70 g, 11 mmol) and Raneynickel slurry (2.5 mL) in 95% ethanol (45 mL) was heated to 55° C. Afterapproximately two hours at 55° C. the reaction was complete as indicatedby LC-MS. The reaction mixture was filtered through Celite, and theRaney nickel was washed with hot methanol. The filtrate was concentratedunder reduced pressure, and the residue was purified by chromatographyto give 0.21 g (44%) of(S)—N-(1-(3-aminophenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamideas a light-yellow oil. MS (EI) for C₂₂H₂₆F₃N₃O: 406 (MH⁺).

Step 3: Preparation ofN-((1S)-1-(3-(2-((tert-butyldimethylsilyl)oxy)propylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamide

(S)—N-(1-(3-aminophenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamide(0.12 g, 0.30 mmol) was dissolved in dichloromethane (5 mL) andanhydrous pyridine (0.18 mL, 2.31 mmol). To the cooled (0° C.) yellowsolution there was added dropwise2-((tert-butyldimethylsilyl)oxy)propane-1-sulfonyl chloride (0.22 g,0.77 mmol) in dichloromethane (1 mL). The yellow reaction mixture wasallowed to stir at 0° C., and the color turned orange. The reactionmixture was allowed to equilibrate to room temperature. Afterapproximately 17 hours at room temperature, the reaction mixture wasdiluted with dichloromethane (25 mL) followed by the addition of water(30 mL). The aqueous portion was extracted with dichloromethane (2×15mL). In five separate washing steps, the combined organic portions werewashed in the following sequence: a 1N hydrochloric acid wash, a waterwash, a saturated sodium bicarbonate wash, a second water wash and abrine wash (35 mL each). The organic portion was dried over anhydroussodium sulfate, filtered, concentrated and purified by chromatography togive 0.14 g (72%) ofN-((1S)-1-(3-(2-((tert-butyldimethylsilyl)oxy)propylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamideas a yellow oil. MS (EI) for C₃₁H₄₆F₃N₃O₄SSi: 642(MH⁺).

Step 4: Preparation ofN-((1S)-1-(3-(2-hydroxypropylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamide,hydrochloride salt

To a solution ofN-((1S)-1-(3-(2-((tert-butyldimethylsilyl)oxy)propylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamide(0.10 g, 0.15 mmol) in tetrahydrofuran (8 mL) at 0° C. was addedtetra-N-butylammonium fluoride (0.46 mL, 0.46 mmol; 1 M intetrahydrofuran). After approximately 17 hours at room temperature thetetrahydrofuran was removed under reduced pressure. The residue waspurified by chromatography to give 0.056 g (68%) ofN-((1S)-1-(3-(2-hydroxypropylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)ethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamideas a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.07-7.55 (m, 8H), 6.05 (m,1H), 4.40 (m, 1H), 3.79-3.93 (m, 2H), 3.22 (m, 2H), 3.03-3.15 (m, 2H),2.90 (m, 1H), 2.76 (s, 3H), 2.61 (m, 2H), 1.79 (m, 3H), 1.65 (m, 2H),1.40 m, 2H), 1.22 (m, 3H); MS (EI) for C₂₅H₃₂F₃N₃O₄S: 528(MH⁺).

The compound was converted into the hydrochloride salt by dissolving theoil in acetonitrile and adding 1N hydrochloric acid. The solution waslyopholized to give the hydrochloride salt as an off-white powder.

Example 14 Preparation of2-(3,4-dichlorophenyl)-N—((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide

Step 1: Preparation of benzyl((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenylethyl)carbamate

A solution of (S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetic acid(2.78 g, 9.75 mmol), (R)-pyrrolidin-3-ol hydrochloride (1.23 g, 9.75mmol) and diisopropylethylamine (5.56 mL, 31.2 mmol) was stirred at roomtemperature for fifteen minutes and then cooled to 0° C.O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(3.87 g, 11.70 mmol) was added and the light-brown reaction mixture wasstirred at 0° C. for one hour, and then equilibrated to roomtemperature. After approximately 17 hours at room temperature the orangemixture was concentrated under reduced pressure. The residue waspurified by chromatography to give 1.80 g (52%) of benzyl((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenylethyl)carbamate as aclear oil. MS (EI) for C₂₀H₂₂N₂O₄: 355 (MH⁺).

Step 2: Preparation of(R)-1-((S)-2-(methylamino)-2-phenylethyl)pyrrolidin-3-ol

Benzyl((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenylethyl)carbamate(1.80 g, 5.08 mmol) was dissolved in anhydrous tetrahydrofuran (75 mL)and cooled to 0° C. To the clear solution was added lithium aluminumhydride (2 M in THF, 5.0 mL, 10.16 mmol) carefully. The cloudy reactionmixture was heated to reflux (oil bath at 70° C.) for two hours, andthen allowed to equilibrate to room temperature. After approximately 18hours at room temperature the mixture was cooled with an ice bath. Theexcess lithium aluminum hydride was quenched with ethyl acetate (25 μL),followed by the addition of water (250 μL), and then followed by theaddition of 4N sodium hydroxide (250 μL). After five minutes water (755μL) was added and followed by stirring for fifteen minutes. A whiteprecipitate was filtered and the filtrate dried over anhydrous sodiumsulfate. After filtration the filtrate was concentrated under reducedpressure. The residue was purified by chromatography to give 0.95 g(85%) of (R)-1-((S)-2-(methylamino)-2-phenylethyl)pyrrolidin-3-ol as alight-yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.30-7.33 (m, 5H), 4.34 (m,1H), 3.58 (m, 1H), 3.42 (m, 2H), 2.79-2.86 (m, 3H), 2.49 (m, 1H),2.33-2.40 (m, 2H), 2.27 (s, 3H), 2.17 (m, 1H), 1.75 (m, 1H)); MS (EI)for C₁₃H₂₀N₂O: 221 (MH⁺).

Step 3: Preparation of2-(3,4-dichlorophenyl)-N—((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide

To a stirring solution of(R)-1-((S)-2-(methylamino)-2-phenylethyl)pyrrolidin-3-ol (0.21 g, 0.97mmol) in dry acetonitrile (5 mL; 0.20M), under nitrogen, was addeddiisopropylethylamine (0.52 mL, 2.93 mmol) and 3,4-dichlorophenylaceticacid (0.20 g, 0.97 mmol). The light-yellow solution was cooled to 0° C.and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.38 g, 1.17 mmol) was added. The light-yellow reaction mixture wasallowed to equilibrate to room temperature, and stirred under nitrogen.After approximately 17 hours at room temperature, the yellow mixture wasconcentrated under reduced pressure. The yellow oil was taken up inethyl acetate and washed with 10% ammonium chloride, saturated sodiumbicarbonate and saturated sodium chloride. The organic portion was driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by chromatography to give 0.26 g(65%) of2-(3,4-dichlorophenyl)-N—((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamideas a light-yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.17-7.43 (m, 8H),6.12 (m, 1H), 4.36 (m, 1H), 3.71-3.82 (m, 2H), 3.19 (m, 1H), 2.87-2.98(m, 2H), 2.71 (s, 3H), 2.57 (m, 2H), 2.17 (m, 1H), 1.77 (m, 1H)); MS(EI) for C₂₁H₂₄C₁₂N₂O₂: 407 (MH⁺).

Example 15 Preparation of2-(2,4-Difluorophenyl)-N-{(1S)-1-[4-(2-hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methylacetamide,hydrochloride salt

Using the synthetic approach schematically outlined below,2-(2,4-difluorophenyl)-N-{(1)-1-[4-(2-hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methylacetamide,hydrochloride salt was prepared.

Step 1: Preparation of(2S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)aceticacid

(S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetic acid (2.67g, 10.0 mmol) was dissolved in 70 mL of dimethylformamide and thesolution was cooled in an ice bath. Sodium hydride (0.88 g, 60% inmineral oil, 22.0 mmol) was added in portions. The mixture was stirredfor thirty minutes before 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.30 g,11.0 mmol) in 30 mL of dimethylformamide was added portionally. Thereaction mixture was stirred at room temperature for 17 hours and thendiluted with ice/water. The mixture was extracted with ethyl acetate (50mL×2). The aqueous layer was cooled in an ice bath and acidified using1.5 M aqueous potassium hydrogen sulfate to pH 2-3. The resultingmixture was extracted with ethyl acetate (100 mL×2). The organic phasewas washed with water, brine, and then dried over sodium sulfate. Theproduct (3.3 g) was obtained after removing the solvent and drying underhigh vacuum (yield: 84%). ¹H NMR (500 MHz, CDCl₃): δ 7.32 (m, 2H), 6.92(m, 2H), 5.55 (m, 0.5H), 5.28 (m, 0.5H), 4.74 (m, 1H), 4.15 (m, 2H),4.05 (m, 1H), 3.90 (m, 1H), 3.85 (m, 1H), 3.55 (m, 1H), 1.85 (m, 1H),1.75 (m, 1H), 1.60 (m, 5H), 1.45 (s, 5H), 1.28 (s, 4H); MS (EI) forC₂₀H₂₉NO₇; 394 (MH⁻).

Step 2: Preparation of tert-butyl((1S)-2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethyl)carbamate

(2S)-2-((Tert-butoxycarbonyl)amino)-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)aceticacid (3.20 g, 8.09 mmol), (s)-pyrrolidin-3-ol (0.78 g, 8.90 mmol), andN,N-diisopropylethylamine (2.07 g, 16.18 mmol) were dissolved in 18 mLof acetonitrile. The mixture was stirred for ten minutes at roomtemperature and then cooled to 0° C.O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(3.12 g, 9.71 mmol) was added into the solution. The reaction mixturewas stirred for two hours under an ice bath and then warmed to roomtemperature for four hours. Dichloromethane (200 mL) was added into thereaction mixture, and the resulting solution was washed with water (200mL×3). The solution was dried over sodium sulfate and concentrated. Theproduct was obtained after drying under vacuum (3.40 g, yield: 90%). ¹HNMR (500 MHz, CDCl₃): δ 7.30 (m, 2H), 6.90 (m, 2H), 5.96 (dd, 1H), 5.30(dd, 1H), 4.70 (m, 1H), 4.45 (m, 1H), 4.15 (m, 1H), 4.05 (m, 1H), 3.90(m, 1H), 3.80 (m, 1H), 3.70 (m, 2H), 3.55 (m, 2H), 3.35 (m, 0.5H), 3.10(m, 0.5H), 1.96 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H), 1.60 (m, 2H), 1.55(m, 3H), 1.40 (s, 9H); MS (EI) for C₂₄H₃₆N₂O₇; 465 (MH⁺).

Step 3: Preparation of(3S)-1-((2S)-2-(methylamino)-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethyl)pyrrolidin-3-ol

Tert-butyl((1S)-2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethyl)carbamate(1.33 g, 2.85 mmol) was dissolved in tetrahydrofuran (20 mL). A 2.0 Mlithium aluminum hydride solution (8.0 mL, 16 mmol) was added into thesolution at room temperature. The mixture was stirred at 65° C. for fourhours. Sodium carbonate (3N solution) was cautiously added untileffervescence ceased. Ethyl acetate (100 mL) was added into the mixture.The solid was filtered out and washed with ethyl acetate (100 mL). Thefiltrate was washed with saturated sodium chloride solution and driedover sodium sulfate. The product was obtained after removing solvent(0.84 g, yield: 71%). ¹H NMR (500 MHz, CDCl₃): δ 7.28 (m, 2H), 6.92 (m,2H), 4.74 (m, 1H), 4.34 (m, 1H), 4.16 (m, 2H), 4.06 (m, 1H), 3.92 (m,1H), 3.84 (m, 1H), 3.55 (m, 2H), 3.02 (m, 1H), 2.85 (m, 1H), 2.65 (m,2H), 2.30 (m, 3H), 2.20 (m, 2H), 1.80 (m, 4H), 1.60 (m, 5H); MS (EI) forC₂₀H₃₂N₂O₄; 365 (MH⁺).

Step 4: Preparation of2-(2,4-difluorophenyl)-N-{(1S)-1-[4-(2-hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methylacetamide,hydrochloride salt

(3S)-1-((2S)-2-(methylamino)-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethyl)pyrrolidin-3-ol(0.073 g, 0.20 mmol), 2-(2,4-difluorophenyl)acetic acid (0.034 g, 0.20mmol), and N,N-diisopropylethylamine (0.051 g, 0.40 mmol) were dissolvedin 3 mL of acetonitrile. The mixture was stirred for ten minutes at roomtemperature and then cooled to 0° C.O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.077 g, 0.24 mmol) was added into the solution. The reaction mixturewas stirred for three hours under an ice-bath. Dichloromethane (150 mL)was added into the reaction mixture and the resultant solution waswashed with water and dried over sodium sulfate. Evaporation of thesolvent and purification of the residue by flash chromatography yieldedproduct (0.091 g, 0.18 mmol). The product was dissolved in 10 mL ofmethanol and then 4-methylbenzenesulfonic acid (0.060 g, 0.35 mmol) wasadded. The mixture was stirred for sixty minutes at room temperature.Dichloromethane (100 mL) was added into the solution. The resultingsolution was washed with 10% of sodium carbonate and water. The organicphase was dried over sodium sulfate. Evaporation of the solvent andpurification of the residue by flash chromatography yielded product as afree base (0.035 g, yield: 46%). ¹H NMR (500 MHz, CDCl₃): δ 7.32 (m,1H), 7.22, 7.09 (dd, 2H), 6.85 (m, 4H), 6.05 (m, 0.87H), 5.05 (m,0.13H), 4.31 (m, 1H), 4.10 (m, 2H), 3.96 (m, 2H), 3.78 (d, 1H), 3.65 (d,1H), 3.20 (m, 2H), 2.95 (m, 1H), 2.75 (m, 5H), 2.40 (m, 2H), 2.20 (m,1H), 1.75 (m, 1H); MS (EI) for C₂₃H₂₈F₂N₂O₄: 435 (MH⁺). The free basewas converted to hydrochloride salt and dried by lyophilization.

Example 16 Preparation ofN-{(1S)-1-[4-(2-Hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methyl-2-(6-methylpyridin-3-yl)acetamide,dihydrochloride salt

Using a synthetic approach similar to the one employed in Example 15,N-{(1S)-1-[4-(2-hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methyl-2-(6-methylpyridin-3-yl)acetamidedihydrochloride salt was prepared. ¹H NMR (500 MHz, CDCl₃): δ 8.84 (s,1H), 7.50 (d, 1H), 7.22 (dd, 2H), 7.12 (d, 1H), 6.90 (d, 2H), 6.20 (m,0.85H), 5.05 (m, 0.15H), 4.35 (m, 1H), 4.10 (m, 2H), 3.96 (m, 2H), 3.85(d, 1H), 3.70 (d, 1H), 3.35 (m, 1H), 3.28 (t, 1H), 2.95 (d, 1H), 2.65(s, 3H), 2.60 (m, 2H), 2.55 (s, 3H), 2.32 (m, 1H), 2.10 (br. 1H), 1.85(m, 1H); MS (EI) for C₂₃H₃₁N₃O₄: 414 (MH⁺).

Example 17 Preparation of2-(3,4-Dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide,hydrochloride salt

2-(3,4-Dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide,hydrochloride salt may be prepared according to the following steps.

Step 1: Synthesis of tert-butyl((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenylethyl)carbamate

tert-Butoxycarbonylamino-phenyl-acetic acid (1.9 g, 7.56 mmol) and4-methylmorpholine (0.99 mL, 8.99 mmol) were dissolved intetrahydrofuran (25 mL). The resultant solution was cooled in anice-bath under stirring for ten minutes. Ethyl chloroformate (0.742 mL,7.56 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture wasstirred for thirty minutes, and then (R)-3-pyrrolidino hydrochloric acidsalt (1.02 g, 8.31 mmol) was added. The mixture was stirred at roomtemperature for 16 hours, and then 50 mL of ethyl acetate was added. Thesolution was washed with water (30 mL×3), dried over sodium sulfate andconcentrated to give tert-butyl{(1S)-2-((3R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenylethyl}carbamate(2.0 g, crude).

Step 2: Synthesis of(R)-1-((S)-2-(methylamino)-2-phenylethyl)pyrrolidin-3-ol

A solution of tert-butyl{(1S)-2-((3R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenylethyl}carbamate(920 mg) in tetrahydrofuran (20 mL) was added drop wise to a stirred 2.0M solution of lithium aluminum hydride (436 mg) in tetrahydrofuran. Themixture was stirred for 0.5 hours at room temperature and then heated at65° C. for four hours. A 3N solution of sodium carbonate was addedcautiously until effervescence ceased. The solid was filtered out andwashed with dichloromethane (40 mL). The filtrate was concentrated andthe residue was dissolved in 50 mL of dichloromethane. The resultingsolution was washed with saturated sodium chloride solution (50 mL) anddried over sodium sulfate.(3R)-1-[(2S)-2-(Methylamino)-2-phenylethyl]pyrrolidin-3-ol was obtainedafter removing solvent (550 mg).

Step 3: Synthesis of2-(3,4-dichlorophenyl)-N—((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide

(3R)-1-[(2S)-2-(Methylamino)-2-phenylethyl]pyrrolidin-3-ol (0.70 g, 2.39mmol), 2-(3,4-dichlorophenyl) acetic acid (460 mg, 2.17 mmol) wasdissolved in acetonitrile (20 mL). Diisopropylethylamine (0.5 mL, 4.34mmol) was added. The mixture was stirred for ten minutes at roomtemperate and then cooled to 0° C. HATU (900 mg, 2.6 mmol) was addedinto the solution. The reaction mixture was stirred overnight. Ethylacetate (50 mL) was added and washed with saturated sodium bicarbonate(2×30 mL), brine (30 mL) and dried over sodium sulfate. Evaporation ofthe solvent afforded the crude (880 mg). Half of the material waspurified by prep HPLC to give the TFA salt (300 mg). After free basingwith sodium bicarbonate, the free base was dissolved in 3 mL ofacetonitrile. To the solution was added 1 mL 1N hydrochloride. Themixture was lyophilized to afford product2-(3,4-Dichlorophenyl)-N-{(1S)-2-((3R)-3-hydroxypyrrolidin-1-yl)-1-phenylethyl}-N-methylacetamideas hydrochloride salt (220 mg). LC-MS (ESI, MH⁺): 407.5.

Step 4: Synthesis of(R)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-ylmethanesulfonate

2-(3,4-Dichlorophenyl)-N-{(1S)-2-((3R)-3-hydroxypyrrolidin-1-yl)-1-phenylethyl}-N-methylacetamide(1.07 g, 2.62 mmol) was dissolved in dichloromethane (10 ml) and cooledto 0° C. Triethylamine (0.73 mL, 5.24 mmol) was added dropwise. Themixture was stirred for ten minutes before methanesulfonic chloride(0.42 mL, 5.24 mmol) was added. The reaction mixture was stirredovernight. Dichloromethane (50 mL) was added and washed with water (2×30mL) and brine (30 mL) and dried over sodium sulfate. Evaporation of thesolvent afforded the crude material methanesulfonic acid(R)-1-((S)-2-{[2-(3,4-dichloro-phenyl)-acetyl]-methyl-amino}-2-phenyl-ethyl)-pyrrolidin-3-ylester (0.78 g) LC-MS (ESI, MH⁺): 485.42.

Step 5: Synthesis of2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide,hydrochloride salt

Methanesulfonic acid(R)-1-((S)-2-{[2-(3,4-dichloro-phenyl)-acetyl]-methyl-amino}-2-phenyl-ethyl)-pyrrolidin-3-ylester (1.0 equivalent) and 2-(2-(2-aminoethoxy)ethoxy)ethanol (1.2equivalent) was dissolved in dimethylformamide (1 mL) and heated at 80 Cfor ten hours. The reaction mixture was purified by prep HPLC withhydrochloric acid buffer to give2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide,hydrochloride salt. LC-MS (ESI, MH⁺): 539.

Example 18 Preparation of1N-{(1S)-1-[4-(2-Hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methyl-2-(1,3-thiazol-2-yl)acetamide,hydrochloride salt

Using a synthetic approach similar to the one employed in Example 15,N-{(1S)-1-[4-(2-Hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methyl-2-(1,3-thiazol-2-yl)acetamidehydrochloride salt was prepared. ¹H NMR (500 MHz, CDCl₃): 7.74 (d, 1H),7.31 (d, 1H), 7.22, 7.12 (d, 2H), 6.87 (d, 2H), 6.05 (m, 0.82H), 5.25(m, 0.18H), 4.30 (m, 2H), 4.10 (m, 3H), 3.96 (m, 2H), 3.20 (m, 2H), 3.00(m, 1H), 2.80 (s, 3H), 2.70 (m, 2H), 2.20 (m, 2H), 1.75 (m, 1H); MS (EI)for C₂₀H₂₇N₃O₄S: 406 (MH⁺).

Example 19 Synthesis of2-(3,4-Dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-hydroxyethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide,hydrochloride salt

Methanesulfonic acid(R)-1-((S)-2-{[2-(3,4-dichloro-phenyl)-acetyl]-methyl-amino}-2-phenyl-ethyl)-pyrrolidin-3-ylester (preparation described in Step 4 of Example 17) (1.0 equivalent)and 2-(2-aminoethoxy)ethanol (1.2 equivalents) were dissolved indimethylformamide (1 mL) and heated at 80 C for ten hours. The reactionmixture was purified by prep HPLC with hydrochloric acid buffer to give2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-hydroxyethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide,hydrochloride salt. LC-MS (ESI, MH⁺): 495.

Example 20 Preparation of2-(2,4-difluorophenyl)-N—((S)-1-(4-(2-hydroxyethoxy)phenyl)-2-((S)-3-(2-hydroxyethoxy)pyrrolidin-1-yl)ethyl)-N-methylacetamide,hydrochloride salt

Using a synthetic approach similar to the one employed in Example 19,2-(2,4-difluorophenyl)-N—((S)-1-(4-(2-hydroxyethoxy)phenyl)-2-((S)-3-(2-hydroxyethoxy)pyrrolidin-1-yl)ethyl)-N-methylacetamide,hydrochloride salt was prepared. δ 7.35 (m, 1H), 7.20, 7.09 (m, 2H),6.85 (m, 4H), 6.05 (m, 0.86H), 5.05 (m, 0.14H), 4.05 (m, 3H), 3.95 (m,2H), 3.60 (m, 4H), 3.50 (m, 2H), 3.15 (m, 1H), 3.02 (m, 1H), 2.60 (m,6H), 2.50 (m, 2H), 2.10 (m, 1H), 1.85 (m, 1H); MS (EI) for C₂₅H₃₂F₂N₂O₅:479 (MH⁺).

Example 21 Preparation of2-(3,4-Difluorophenyl)-N-{(1S)-1-[4-(2-hydroxyethoxy)phenyl]-2-[(3S)-3-(2-hydroxyethoxy)pyrrolidin-1-yl]ethyl}-N-methylacetamide,hydrochloride salt

Using a synthetic approach similar to the one employed in Example 19,2-(3,4-difluorophenyl)-N-{(1S)-1-[4-(2-hydroxyethoxy)phenyl]-2-[(3S)-3-(2-hydroxyethoxy)pyrrolidin-1-yl]ethyl}-N-methylacetamide,hydrochloride salt was prepared. δ 7.20 (d, 2H), 7.15 (m, 2H), 7.02 (m,1H), 6.88 (d, 2H), 6.06 (m, 0.83H), 5.05 (m, 0.17H), 4.06 (m, 3H), 3.96(m, 2H), 3.75 (m, 4H), 3.50 (m, 2H), 3.18 (t, 1H), 2.95 (m, 2H), 2.55(m, 5H), 2.40 (m, 2H), 2.10 (m, 1H), 1.80 (m, 1H); MS (EI) forC₂₅H₃₂F₂N₂O₅: 479 (MH⁺).

Example 22 Preparation of1-(3,4-Dichlorophenyl)-N-{(1S)-1-[4-(2-hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methylmethanesulfonamide,hydrochloride salt

(3S)-1-((2S)-2-(Methylamino)-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethyl)pyrrolidin-3-ol(0.072 g, 0.20 mmol) (preparation described in Step 3 of Example 15),(3,4-dichlorophenyl)methanesulfonyl chloride (0.051 g, 0.20 mmol), andN,N-diisopropylethylamine (0.07 mL) were dissolved in 10 mL ofdichloromethane. The mixture was stirred for three hours at 0° C. andthen warmed to room temperature overnight. Dichloromethane (50 mL) wasadded into the mixture. The resultant solution was washed with water anddried over sodium sulfate. The solvent was removed and the residue waspurified by flash chromatography. From this residue, 0.040 g (0.068mmol, yield: 35%) of the target intermediate was obtained, which wasdissolved in 10 mL of methanol. 4-Methylbenzenesulfonic acid (0.026 g,0.14 mmol) was added into the solution and the mixture was stirred forone hour at room temperature. Dichloromethane (50 mL) was added into thesolution and washed with sodium carbonate solution (10%), water, anddried over sodium sulfate. Evaporation of the solvent and purificationof the residue by flash chromatography yielded the named product as afree base (0.020 g, yield: 58%). ¹H NMR (500 MHz, CDCl₃): δ 7.42 (d,1H), 7.38 (s, 1H), 7.22 (d, 1H), 7.08 (d, 2H), 6.88 (d, 2H), 5.15 (m,1H), 4.35 (m, 1H), 4.30 (m, 2H), 4.10 (m, 2H), 4.00 (m, 2H), 3.30 (m,2H), 2.82 (m, 1H), 2.74 (m, 1H), 2.63 (m, 1H), 2.43 (s, 3H), 2.20 (m,3H), 1.80 (m, 1H); MS (EI) for C₂₂H₂₈C₁₂N₂O₅S: 503 (MH⁺). The free basewas converted to hydrochloride salt and dried by lyophilization.

Example 23 Preparation ofN-{(1S)-1-[4-(2-Hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methyl-1-[4-(trifluoromethyl)phenyl]methanesulfonamide,hydrochloride salt

Using a synthetic approach similar to the one employed in Example 22,N-{(1S)-1-[4-(2-hydroxyethoxy)phenyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-N-methyl-1-[4-(trifluoromethyl)phenyl]methanesulfonamide,hydrochloride salt was prepared. ¹H NMR (500 MHz, CDCl₃): δ 7.60 (d,2H), 7.45 (d, 2H), 7.00 (d, 2H), 6.85 (d, 2H), 5.12 (m, 1H), 4.40 (m,3H), 4.10 (m, 2H), 3.98 (m, 2H), 3.30 (m, 2H), 2.80 (d, 1H), 2.74 (m,1H), 2.65 (m, 1H), 2.50 (s, 3H), 2.20 (m, 3H), 1.80 (m, 1H); MS (EI) forC₂₃H₂₉F₃N₂O₅S: 503 (MH⁺).

Example 24 Preparation of(S)-2-(3,4-dichlorophenyl)-N-(2-(3-hydroxyazetidin-1-yl)-1-(4-(2-hydroxyethoxy)phenyl)ethyl)-N-methylacetamide,hydrochloride salt

Using the synthetic approach schematically outlined below,(S)-2-(3,4-dichlorophenyl)-N-(2-(3-hydroxyazetidin-1-yl)-1-(4-(2-hydroxyethoxy)phenyl)ethyl)-N-methylacetamide,hydrochloride salt was prepared.

Step 1: Preparation of tert-butyl((1S)-2-(3-hydroxyazetidin-1-yl)-2-oxo-1-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethyl)carbamate

(2S)-2-((Tert-butoxycarbonyl)amino)-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)aceticacid (0.80 g, 2.02 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.78 g, 2.43 mmol) were dissolved in 10 mL of dimethylformamide.N,N-Diisopropylethylamine (0.78 g, 6.07 mmol) and 3-hydroxyazetidinehydrochloride (0.33 g, 3.0 mmol) were added. The mixture was stirred atroom temperature for one hour. Dichloromethane (100 mL) was added, andthe resulting solution was washed with water (100 mL×3). The solutionwas dried over sodium sulfate and concentrated. The residue was purifiedby flash chromatography (0.60 g, yield: 66%). ¹H NMR (500 MHz, CDCl₃): δ7.18 (m, 2H), 6.80 (m, 2H), 5.34 (m, 1H), 5.00 (m, 2H), 4.62 (m, 1H),4.55 (m, 0.5H), 4.35 (m, 1H), 4.15 (m, 0.5H), 4.00 (m, 4H), 3.90 (m,0.5H), 3.80 (m, 1H), 3.72 (m, 1H), 3.58 (m, 0.5H), 3.45 (m, 1H), 2.65(m, 1H), 1.75 (m, 1H), 1.65 (m, 1H), 1.50 (m, 4H), 1.30 (s, 9H); MS (EI)for C₂₃H₃₄N₂O₇: 451 (MH⁺).

Step 2: Preparation of1-((2S)-2-(methylamino)-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethyl)azetidin-3-ol

Tert-butyl((1S)-2-(3-hydroxyazetidin-1-yl)-2-oxo-1-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethyl)carbamate(0.335 g, 0.744 mmol) was dissolved in tetrahydrofuran (10 mL). A 2.0lithium aluminum hydride solution (2.0 mL, 4 mmol) was added into thesolution at room temperature. The mixture was stirred at 65° C. for fourhours. A 3N solution of sodium carbonate was added cautiously untileffervescence ceased. Ethyl acetate (100 mL) was added into the mixture.The solid was filtered out and washed with ethyl acetate (50 mL). Thefiltrate was washed with saturated sodium chloride solution and driedover sodium sulfate. The product was obtained after removing solvent(0.2 g, yield: 77%). MS (EI) for C₁₉H₃₀N₂O₄: 351 (MH⁺).

Step 3: Preparation of(S)-2-(3,4-dichlorophenyl)-N-(2-(3-hydroxyazetidin-1-yl)-1-(4-(2-hydroxyethoxy)phenyl)ethyl)-N-methylacetamide,hydrochloride salt

1-((2S)-2-(Methylamino)-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)ethyl)azetidin-3-ol(0.140 g, 0.40 mmol), 3,4-dichlorophenylacetic acid (0.081 g, 0.40mmol), and N,N-diisopropylethylamine (0.104 g, 0.80 mmol) were dissolvedin 3 mL of acetonitrile. The mixture was stirred for ten minutes at roomtemperature and then cooled to 0° C.O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.153 g, 0.477 mmol) was added into the solution. The reaction mixturewas stirred for one hour under an ice-bath. Dichloromethane (100 mL) wasadded into the mixture. The resulting solution was washed with water anddried over sodium sulfate. Evaporation of the solvent and purificationof the residue by flash chromatography yielded a product (0.091 g, yield43%). This product (0.056 g, 0.10 mmol) and 4-methylbenzenesulfonic acid(0.035 g, 0.21 mmol) were dissolved in 10 mL of methanol. The mixturewas stirred for sixty minutes at room temperature. Evaporation of thesolvent and purification of the residue by flash chromatography yieldedthe named product as free base (0.028 g, yield 42.3%). ¹H NMR (500 MHz,MeOD): δ 7.50 (m, 2H), 7.25 (m, 1H), 7.20 (m, 2H), 7.00 (d, 2H), 6.05(m, 1H), 4.68 (m, 1H), 4.50 (m, 2H), 4.10 (m, 4H), 4.00 (m, 1H), 3.90(m, 4H), 3.80 (m, 1H), 2.75 (s, 3H); MS (EI) for C₂₂H₂₆C₁₂N₂O₄: 453(MH⁺). The free base was converted to hydrochloride salt and dried bylyophilization.

Example 25 Preparation of2-(3,4-dichlorophenyl)-N-methyl-N—((S)-2-((S)-3-morpholinopyrrolidin-1-yl)-1-phenylethyl)acetamide,hydrochloride salt

2-(3,4-Dichlorophenyl)-N-methyl-N—((S)-2-((S)-3-morpholinopyrrolidin-1-yl)-1-phenylethyl)acetamidewas synthesized according to the following steps Step 1: Preparation of(S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetic acid

To a solution (S)-2-amino-2-phenylacetic acid (20 g, 0.132 mol) in water(500 mL) was added Na₂CO₃ (27.97 g, 0.264 mol) and NaHCO₃ (11.1 g, 0.132mol) at ambient temperature. The mixture was stirred to give a clearsolution. Acetone (40 mL) was added and the slightly turbid solution wascooled in an ice water bath to 15-20° C. Cbz-Cl (28.15 g, 0.165 mol) wasadded slowly, with stirring, and the reaction mixture allowed to warm toambient temperature. After stirring for an additional three hours, themixture was extracted with MTBE (100 mL). The pH of an aqueous layer wasadjusted to 2 using aqueous HCl. The resulting oil was extracted intoEtOAc (100 mL×2). The combined organic layer was washed with H₂O andthen concentrated in vacuo to give(S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetic acid (30.2 g, 80%yield) as a white color solid.

Step 2: Preparation of benzyl((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenylethyl) carbamate

(S)-2-(((Benzyloxy)carbonyl)amino)-2-phenylacetic acid (10.36 g, 36.3mmol), (R)-pyrrolidin-3-ol (3.48 g, 39.93 mmol) and DIPEA (14.0 g, 108.9mmol) were dissolved in acetonitrile (80 mL). The mixture was stirredfor 15 minutes at 22-25° C. and then cooled to 0° C.O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (14.0 g, 43.56 mmol) was added into the solution. The reactionmixture was stirred for one hour at 0° C. and then for four hours atambient temperature. The reaction mixture was concentrated under reducedpressure. The resulting residue was dissolved in DCM (50 mL) and washedwith brine (25 mL×2). The solution was dried over anhydrous sodiumsulfate and concentrated. The obtained residue was purified by columnchromatography yielded((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenylethyl) carbamate(7.5 g, 58% yield).

Step 3: Preparation of(R)-1-((S)-2-(methylamino)-2-phenylethyl)pyrrolidin-3-ol

((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenylethyl) carbamate(7.0 g, 19.75 mmol) was dissolved in THF (55 mL). The mixture was thencooled to 0° C. and LAH (3.74 g, 98.75 mmol) was added. The mixture wasstirred for 15 minutes at 0° C., followed by stirring for 16 hours at65° C. The reaction mass was cooled to 0° C. and 3N aq. sodium carbonatesolution (150 mL) was added (cautiously) until effervescence ceased. Aprecipitated solid was filtered and washed with EtOAc (100 mL). Thefiltrate was concentrated and the residue was dissolved in EtOAc (150mL). The product was extracted into 1N aq. HCl (2×25 mL) and washed withMTBE (3×15 mL). The pH of the aqueous layer was adjusted to 9, and theproduct was extracted into EtOAc. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated under vacuumto obtain a crude compound. The crude compound, upon purification usingcolumn chromatography yielded(R)-1-((S)-2-(methylamino)-2-phenylethyl)pyrrolidin-3-ol (2.5 g, 58%yield).

Step 4: Preparation of2-(3,4-dichlorophenyl)-N—((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide

To a solution of(R)-1-((S)-2-(methylamino)-2-phenylethyl)pyrrolidin-3-ol (2.5 g, 11.35mmol) in ACN (40 mL) were added 3,4-dichlorophenyl acetic acid (2.56 g,12.48 mmol), HOBt.H₂O (1.84 g, 13.62 mmol), DIPEA (2.2 g, 17.02 mmol)and EDC.HCl (3.26 g, 17.02 mmol) at ambient temperature. The mixture wasstirred for two hours and ACN was distilled off. The crude compound,dissolved in DCM (25 mL), was washed with 10% Na₂CO₃ (4×25 mL), 10%NH₄Cl (4×25 mL), and brine (25 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. The resultantgummy mass upon purification by column chromatography yielded2-(3,4-dichlorophenyl)-N—((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide(2.9 g, 63% yield).

Step 5: Preparation of(R)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-ylmethanesulfonate

To a solution of2-(3,4-dichlorophenyl)-N—((S)-2-((R)-3-hydroxypyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide(0.5 g, 1.23 mmol) in DCM (5 mL) were added TEA (1.48 mmol) and MsCl(1.35 mmol) at ambient temperature. The mixture was stirred for twohours and quenched with H₂O (10 mL). The organic layer was separated andwashed with 5% aq. NH₄C₁ (5 mL×2) followed by brine (5 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum to give(R)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-ylmethanesulfonate (0.53 g, 90% yield) as a light yellow color gum.

Step 6: Preparation ofN—((S)-2-((S)-3-azidopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide

To a solution of(R)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-ylmethanesulfonate (0.5 g, 1.03 mmol) in DMF (5 mL) was added NaN₃ (0.1 g,1.54 mmol). The mixture was heated to 60° C. for three hours. Aftercooling down to ambient temperature, the mixture was concentrated underreduced pressure, treated with H₂O (10 mL) and extracted with DCM (10mL×2). The combined organic layer was washed with brine (20 mL) andconcentrated under vacuum to affordN—((S)-2-((S)-3-azidopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(0.39 g, 88% yield) as brown color gum.

Step 7: Preparation ofN—((S)-2-((S)-3-aminopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide

A solution ofN—((S)-2-((S)-3-azidopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(0.35 g, 0.81 mmol) and H₂O (87 μL, 4.86 mmol) in THF (3.5 mL) wascooled with an ice-bath at 0° C. PPh₃ (0.425 g, 1.62 mmol) was addedinto the mixture as a solid in small portions. After the addition, themixture was slowly warmed to ambinet temperature and then heated to 50°C. for five hours. After five hours, the mixture was concentrated invacuum and mixed with H₂O (7 mL) and DCM (10 mL) and then acidified with1N HCl to pH 2. The mixture was washed with DCM (10 mL×2) and theaqueous phase was then treated with 6N NaOH to maintain pH 10. Afterextraction with DCM (10 mL×3), the organic layers were combined andwashed with brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under vacuum to giveN—((S)-2-((S)-3-aminopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(0.23 g, 70% yield) as light yellow color gum.

Step 8: Preparation of2-(3,4-dichlorophenyl)-N-methyl-N—((S)-2-((S)-3-morpholinopyrrolidin-1-yl)-1-phenylethyl)acetamide

To a solution ofN—((S)-2-((S)-3-aminopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(640 mg, 1.58 mmol) in 1,4-dioxane:H₂O (5 vol) were added1-bromo-2-(2-(trifluoromethoxy)ethoxy)ethane (450 mg, 1.90 mmol), sodiumlauryl sulphate (45 mg, 0.158 mmol) and K₂CO₃ (530 mg, 4.79 mmol). Themixture was heated to 80° C. for sixteen hours. After sixteen hours, themixture was concentrated in vacuum and the crude was dissolved in EtOAc(10 mL). The organic layer was washed with water (10 mL) and brine (10mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum to give acrude product. The crude product was purified by column chromatographyto yield2-(3,4-dichlorophenyl)-N-methyl-N—((S)-2-((S)-3-morpholinopyrrolidin-1-yl)-1-phenylethyl)acetamide(80 mg, 11% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.42-7.36 (m, 2H),7.35-7.24 (m, 4.6H), 7.18-7.12 (m, 1.4H), 6.1 (m, 0.8H), 4.98 (m, 0.2H),3.8-3.6 (m, 6H), 3.15-2.9 (m, 2H), 2.84-2.65 (m, 7H), 2.5-2.32 (m, 5H),2.1-1.9 (m, 1H), 1.75-1.64 (m, 1H); MS (EI) for C₂₅H₃₁C₁₂N₃O₂: 476(MH⁺). The free base was dissolved in 4M hydrochloride in 2-propanol.The mixture was concentrated to afford product as hydrochloride salt.

Example 26 Preparation ofN,N′-((1S,1'S)-((3S,3'S)-3,3′-(ethane-1,2-diylbis(azanediyl))bis(pyrrolidine-3,1-diyl))bis(1-phenylethane-2,1-diyl))bis(2-(3,4-dichlorophenyl)-N-methylacetamide),hydrochloride salt

N,N′-((1S,1'S)-((3S,3'S)-3,3′-(ethane-1,2-diylbis(azanediyl))bis(pyrrolidine-3,1-diyl))bis(1-phenylethane-2,1-diyl))bis(2-(3,4-dichlorophenyl)-N-methylacetamide)was synthesized according to the following steps. To a solution ofN—((S)-2-((S)-3-aminopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(640 mg, 1.58 mmol) in 1,4-dioxane:H₂O (5 vol) were added1-bromo-2-(2-(trifluoromethoxy)ethoxy)ethane (450 mg, 1.90 mmol), sodiumlauryl sulphate (45 mg, 0.158 mmol) and K₂CO₃ (530 mg, 4.79 mmol). Themixture was heated to 80° C. for sixteen hours. After sixteen hours, themixture was concentrated in vacuum and the crude was dissolved in EtOAc(10 mL). The organic layer was washed with water (10 mL) and brine (10mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum to give acrude product. The crude product was purified by column chromatographyto yieldN,N′-((1S,1'S)-((3S,3'S)-3,3′-(ethane-1,2-diylbis(azanediyl))bis(pyrrolidine-3,1-diyl))bis(1-phenylethane-2,1-diyl))bis(2-(3,4-dichlorophenyl)-N-methylacetamide).(180 mg). ¹H NMR (500 MHz, CDCl₃): δ 7.4-7.2 (m, 12H), 7.18-7.09 (m,4H), 6.1 (m, 1.6H), 5.1 (m, 0.4H), 4.52-4.12 (m, 4H), 3.8-3.6 (m, 4.6H),3.12-2.94 (m, 4H), 2.82-2.62 (m, 13.4H), 2.6-2.5 (m, 2H), 2.38-2.18 (m,4H), 1.6-1.5 (m, 2H); MS (EI) for C₄₄H₅₂C₁₄N₆O₂: 839 (MH⁺). The freebase was dissolved in 4M hydrochloride in 2-propanol. The mixture wasconcentrated to afford product as hydrochloride salt.

Example 27 Synthesis of2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-((2-hydroxyethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide,hydrochloride salt

Methanesulfonic acid(R)-1-((S)-2-{[2-(3,4-dichloro-phenyl)-acetyl]-methyl-amino}-2-phenyl-ethyl)-pyrrolidin-3-ylester (preparation described in Step 4 of Example 17) (0.257 g, 0.53mmol) and aminoethanol (0.038 mL, 0.62 mmol) was dissolved indimethylformamide (1 mL) and heated at 80 C for ten hours. The reactionmixture was purified by prep HPLC to give2-(3,4-dichloro-phenyl)-N—{(S)-2-[(S)-3-(2-hydroxy-ethylamino)-pyrrolidin-1-yl]-1-phenyl-ethyl}-N-methyl-acetamide,hydrochloride salt. LC-MS (ESI, MH⁺): 450.45.

Example 28 Preparation of2-(3,4-dichlorophenyl)-N-methyl-N—((S)-1-phenyl-2-((S)-3-((2-(2-(trifluoromethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)ethyl)acetamide,dihydrochloride salt

2-(3,4-Dichlorophenyl)-N-methyl-N—((S)-1-phenyl-2-((S)-3-((2-(2-(trifluoromethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)ethyl)acetamide,dihydrochloride salt was synthesized according to the following step.

To a solution ofN—((S)-2-((S)-3-aminopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(640 mg, 1.58 mmol) in 1,4-dioxane:H₂O (5 vol) were added1-bromo-2-(2-(trifluoromethoxy)ethoxy)ethane (450 mg, 1.90 mmol), sodiumlauryl sulphate (45 mg, 0.158 mmol) and K₂CO₃ (530 mg, 4.79 mmol). Themixture was heated to 80° C. for sixteen hours. After sixteen hours, themixture was concentrated in vacuum and the crude was dissolved in EtOAc(10 mL). The organic layer was washed with water (10 mL) and brine (10mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum to give acrude product. The crude product was purified by column chromatographyto yield2-(3,4-dichlorophenyl)-N-methyl-N—((S)-1-phenyl-2-((S)-3-((2-(2-(trifluoromethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)ethyl)acetamide(0.091 g, 12% yield).

¹H NMR (500 MHz, CDCl₃): δ 7.42-7.36 (m, 2H), 7.35-7.24 (m, 4H),7.18-7.12 (m, 2H), 6.1 (m, 1H), 3.8-3.6 (m, 6H), 3.15-2.98 (m, 2H),2.8-2.65 (m, 7H), 2.5-2.32 (m, 5H), 1.95 (m, 1H), 1.75-1.64 (m, 1H); MS(EI) for C₂₈H₃₂C₁₂F₃N₃O₃: 563 (MH⁺). The free base was dissolved in 4Mhydrochloride in 2-propanol. The mixture was concentrated to afford theproduct as a dihydrochloride salt.

Example 29 Synthesis of2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-methoxyethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide,dihydrochloride salt

2-(3,4-Dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-methoxyethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamidehydrochloride was synthesized according to the following step.

To a solution ofN—((S)-2-((S)-3-aminopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(500 mg, 1.23 mmol) in 1,4-dioxane:H₂O (5 mL) was added1-bromo-2-(2-methoxyethoxy)ethane (66 mg, 0.407 mmol), sodium laurylsulfate (35.47 mg, 0.123 mmol) and K₂CO₃ (153 mg, 1.11 mmol). Themixture was heated to 90° C. for eighteen hours. After eighteen hours,the mixture was concentrated and the aqueous layer was extracted intoEtOAc (15 mL). The organic layer was washed with brine (10 mL), driedover anhydrous Na₂SO₄ and concentrated under vacuum to give a crudeproduct. The crude product was purified by column chromatography toyield2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-methoxyethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamidehydrochloride (60 mg). ¹H NMR of free base (500 MHz, DMSO-d₆): δ 7.6 (m,1H), 7.40-7.2 (m, 7H), 5.85 (m, 1H), 3.9 (m, 2H), 3.70-3.45 (m, 10H),3.32 (s, 3H), 3.24 (m, 2H), 3.04 (m, 1H), 2.55-2.75 (m, 2H), 2.8 (s,3H), 2.30 (m, 1H), 1.25 (m, 2H); MS (EI) for C₂₆H₃₅C₁₂N₃O₃: 508.2659(MH⁺). The free base was dissolved in 4M hydrochloride in 2-propanol.The mixture was concentrated to afford product as a dihydrochloridesalt.

Example 30 Preparation of2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-(2-(2-ethoxyethoxy)ethoxy)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide,hydrochloride salt

2-(3,4-Dichlorophenyl)-N—((S)-2-((S)-3-(2-(2-ethoxyethoxy)ethoxy)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamidehydrochloride was synthesized according to the following steps.

Step 1: Preparation of(S)-3-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethoxy)pyrrolidine

(S)-tert-Butyl 3-hydroxypyrrolidine-1-carboxylate (6.0 g, 32.04 mmol)was dissolved in THF (120 mL). To the above mixture, K^(t)OBu (3.60 g,32.04 mmol) was added and the reaction mixture was heated to 65° C. fortwo hours. The mixture was cooled to ambient temperature.2-(2-(2-(Trifluoromethoxy)ethoxy)ethoxy)ethyl methanesulfonate (9.49 g,32.04 mmol) was added and stirred for eighteen hours. The above mixturewas concentrated under reduced pressure. The residue was dissolved inDCM (120 mL) and the resulting solution was washed with water (50 mL×2).The organic layer was dried over anhyhydrous Na₂SO₄ and concentratedunder vacuum to obtain a thick oil. The oil was dissolved in DCM/TFA(2:1) (25 mL) and stirred for four hours at ambient temperature and thenconcentrated under vacuum. The residue was dissolved in water (35 mL)and the pH of the mixture was adjusted to 9 using 10% aqueous Na₂CO₃.The aqueous layer was extracted with DCM (50 mL×3). The combined DCMlayers were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude was purified by column chromatography and yielded(S)-3-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethoxy) pyrrolidine (2.0g, 21% yield) as an oil.

Step 2: Preparation of benzyl((S)-2-oxo-1-phenyl-2-((S)-3-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethoxy)pyrrolidin-1-yl)ethyl)carbamate

(S)-3-(2-(2-(2-(Trifluoromethoxy)ethoxy)ethoxy)ethoxy)pyrrolidine (1.1g, 3.83 mmol), (S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetic acid(1.092 g, 3.83 mmol) and DIPEA (1.485 g, 11.49 mmol) were dissolved inACN (10 mL). The above mixture was stirred for fifteen minutes atambient temperature and then cooled to 0° C.O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (1.475 g, 4.59 mmol) was added into the solution and stirred forone hour at 0° C. and for four hours at ambient temperature. After fourhours, the mixture was concentrated under reduced pressure. The residuethus obtained was dissolved in DCM (50 mL) and washed with brine (25mL×2). The DCM layer was dried over anhydrous Na₂SO₄ and concentrated.The crude compound was purified by column chromatography and yieldedbenzyl((S)-2-oxo-1-phenyl-2-((S)-3-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethoxy)pyrrolidin-1-yl)ethyl)carbamate(1.0 g, 47% yield).

Step 3: Preparation of(S)-2-((S)-3-(2-(2-ethoxyethoxy)ethoxy)pyrrolidin-1-yl)-N-methyl-1-phenylethanamine

To a three neck round bottom flask, benzyl((S)-2-oxo-1-phenyl-2-((S)-3-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethoxy)pyrrolidin-1-yl)ethyl)carbamate (1.0 g, 1.803 mmol) was dissolved in THF(10 mL) under a nitrogen atmosphere. The above mixture was cooled to 0°C. and an LAH tablet (0.342 g, 9.02 mmol) was added and stirred forfifteen minutes at 0° C. and then heated to 65° C. for four hours. A 3Naq. Na₂CO₃ solution was added slowly until effervescence ceased. Theprecipitated solid was filtered and washed with DCM (100 mL). Thefiltrate was concentrated and the residue was dissolved in DCM (150 mL),washed with brine, dried over anhydrous Na₂SO₄ and concentrated undervacuum to get(S)-2-((S)-3-(2-(2-ethoxyethoxy)ethoxy)pyrrolidin-1-yl)-N-methyl-1-phenylethanamine(1.0 g, 49% yield).

Step 4: Preparation of 2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-(2-(2ethoxyethoxy)ethoxy)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamidehydrochloride

To a three neck round bottom flask(S)-2-((S)-3-(2-(2-ethoxyethoxy)ethoxy)pyrrolidin-1-yl)-N-methyl-1-phenylethanamine(300 mg, 0.892 mmol), 2-(3,4-dichlorophenyl)acetic acid (183 mg, 0.892mmol), and DIPEA (346 mg, 2.67 mmol) were dissolved in ACN (10 mL). Themixture was stirred for fifteen minutes at ambient temperature and thencooled to 0° C. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (343 mg, 1.070 mmol) was added into thesolution. The resulting mixture was stirred for eighteen hours atambient temperature. After eighteen hours, the reaction mixture wasconcentrated and the residue was dissolved in DCM (100 mL). The organiclayer was washed with H₂O, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue thus obtained was purified by flashcolumn chromatography and yielded2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-(2-(2-ethoxyethoxy)ethoxy)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide(150 mg, 32% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.40 (m, 2H), 7.32 (m,2H), 7.25 (m, 2H), 7.20-7.10 (m, 2H), 6.10 (m, 1H), 4.25 (m, 2H), 4.1(br, s, 1H), 3.85 (br, s, 1H), 3.65 (m, 12H), 3.4-3.3 (m, 1H), 3.2 (br,s, 1H), 2.9-2.8 (br, s, 3H), 2.40 (m, 1H), 2.2 (m, 1H), 2.0 (m, 1H); MS(EI) for C₂₇H₃₆C₁₂N₂O₄: 523 (MH⁺). The free base was dissolved in 4Mhydrochloride in 2-propanol. The mixture was concentrated to afford2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-(2-(2-ethoxyethoxy)ethoxy)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamidehydrochloride.

Example 31 (Prophetic) Synthesis of2-(2-(2-(((S)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-yl)amino)ethoxy)ethoxy)aceticacid

A solution of2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide(preparation described in Example 17) (1.0 equivalent) and reagent-gradeacetone is placed in a flask under nitrogen and cooled to 0° C. To thestirred solution is added dropwise a solution consisting of Jonesreagent and reagent-grade acetone. The Jones solution is added over aperiod of about 20 minutes. Isopropyl alcohol is then added dropwise todestroy excess Jones reagent. The reaction mixture is extracted twicewith diethyl ether, and the combined ether extracts are washed (water,sodium bicarbonate, and saturated sodium chloride), dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue ispurified by chromatography to give2-(2-(2-(((S)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-yl)amino)ethoxy)ethoxy)aceticacid.

Example 32 (Prophetic) Synthesis of2-(2-(((S)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-yl)amino)ethoxy)aceticacid

A solution of2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-((2-(2-hydroxyethoxy)ethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide(preparation described in Example 19) (1.0 equivalent) and reagent-gradeacetone is placed in a flask under nitrogen and cooled to 0° C. To thestirred solution is added dropwise a solution consisting of Jonesreagent and reagent-grade acetone. The Jones solution is added over aperiod of about 20 minutes. Isopropyl alcohol is then added dropwise todestroy excess Jones reagent. The reaction mixture is extracted twicewith diethyl ether, and the combined ether extracts are washed (water,sodium bicarbonate, and saturated sodium chloride), dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue ispurified by chromatography to give2-(2-(((S)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-yl)amino)ethoxy)aceticacid.

Example 33 (Prophetic) Synthesis of2-(((S)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-yl)amino)aceticacid

A solution of2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-((2-hydroxyethyl)amino)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide(1.0 equivalent) and reagent-grade acetone is placed in a flask undernitrogen and cooled to 0° C. To the stirred solution is added dropwise asolution consisting of Jones reagent and reagent-grade acetone. TheJones solution is added over a period of about 20 minutes. Isopropylalcohol is then added dropwise to destroy excess Jones reagent. Thereaction mixture is extracted twice with diethyl ether, and the combinedether extracts are washed (water, sodium bicarbonate, and saturatedsodium chloride), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue is purified by chromatography togive2-(((S)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)pyrrolidin-3-yl)amino)aceticacid.

Example 34 (Prophetic) Preparation of2-(3,4-dichlorophenyl)-N-methyl-N—((S)-1-phenyl-2-((S)-3-((2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)ethyl)acetamide,hydrochloride salt

2-(3,4-dichlorophenyl)-N-methyl-N—((S)-1-phenyl-2-((S)-3-((2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)ethyl)acetamidewas synthesized according to the following steps. A solution ofN—((S)-2-((S)-3-aminopyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(640 mg, 1.58 mmol) in 1,4-dioxane:H₂O (5 vol) containing sodium laurylsulphate (45 mg, 0.158 mmol) and K₂CO₃ (530 mg, 4.79 mmol) is reactedwith 1-bromo-2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethane (450 mg,1.90 mmol) at 80° C. for sixteen hours. After completion of thereaction, the crude compound is purified by column chromatography toafford2-(3,4-dichlorophenyl)-N-methyl-N—((S)-1-phenyl-2-((S)-3-((2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)amino)pyrrolidin-1-yl)ethyl)acetamide.The free base is then reacted with 4M HCl in IPA to afford the productas a hydrochloride salt.

Example 35 (Prophetic) Preparation ofN—((S)-2-((2S,4R)-2-(5,8,11-trioxa-2-azadodecyl)-4-hydroxypyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide,dihydrochloride salt

N—((S)-2-((2S,4R)-2-(5,8,11-trioxa-2-azadodecyl)-4-hydroxypyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamideis synthesized according to the following steps.

Step 1: Preparation of (2S,4R)-methyl1-((S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetyl)-4-hydroxypyrrolidine-2-carboxylate

A mixture of (S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetic acid (1equiv), TBTU (1.1 equiv) and DIPEA (3 equiv) is reacted with(2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.1 equiv) in ACN forsixteen hours. After completion of the reaction, the crude is purifiedby column chromatography to afford (2S,4R)-methyl1-((S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetyl)-4-hydroxypyrrolidine-2-carboxylate.

Step 2: Preparation of (2S,4R)-methyl1-((S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-2-carboxylate

A mixture of (2S,4R)-methyl1-((S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetyl)-4-hydroxypyrrolidine-2-carboxylate(1 equiv) is reacted with 3,4-dihydro-2H-pyran (1.10 equiv) in presenceof PTSA (0.1 equiv) in dichloromethane. After completion of thereaction, the crude is purified by column chromatography to afford(2S,4R)-methyl1-((S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-2-carboxylate.

Step 3: Preparation of((2S,4R)-1-((S)-2-(methylamino)-2-phenylethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methanol

A solution of (2S,4R)-methyl1-((S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-2-carboxylate(1 equiv) in THF is reacted with LAH (5 equiv) at 60° C. for sixteenhours. After completion of the reaction the mixture is quenched withwater under cold conditions and is extracted into EtOAc. The organiclayer is concentrated under vacuum to obtain a crude product, which uponfurther purification using column chromatography affords((2S,4R)-1-((S)-2-(methylamino)-2-phenylethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methanol.

Step 4: Preparation of2-(3,4-dichlorophenyl)-N-((1S)-2-((2S,4R)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide

A mixture of((2S,4R)-1-((S)-2-(methylamino)-2-phenylethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methanol(1 equiv), TBTU (1.2 equiv) and DIPEA (3 equiv) in ACN is reacted with2-(3,4-dichlorophenyl)acetic acid (1.1 equiv) for sixteen hours atambient temperature. After completion of the reaction, the crudecompound is purified by column chromatography to afford2-(3,4-dichlorophenyl)-N-((1S)-2-((2S,4R)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide.

Step 5: Preparation of((2S,4R)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methylmethanesulfonate

A solution of2-(3,4-dichlorophenyl)-N-((1S)-2-((2S,4R)-2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-1-yl)-1-phenylethyl)-N-methylacetamide(1 equiv.) and TEA (1.20 equiv.) in dichloromethane is reacted with MsCl(1.10 equiv.) for two hours at ambient temperature. After completion ofthe reaction, the mixture is washed with water and concentrated undervacuum to afford((2S,4R)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methylmethanesulfonate.

Step 6: Preparation ofN-((1S)-2-((2S,4R)-2-(5,8,11-trioxa-2-azadodecyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide

A mixture of((2S,4R)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-phenylethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methylmethanesulfonate (1 equiv), TEA (1.20 equiv) in DMF, is reacted with2-(2-(2-methoxyethoxy)ethoxy)ethanamine (1.1 euiv) for eight hours.After completion of the reaction, the mixture is quenched in water. Thecompound is extracted into EtOAc twice. The combined EtOAc layer iswashed with water and concentrated under vacuum to affordN-((1S)-2-((2S,4R)-2-(5,8,11-trioxa-2-azadodecyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide.

Step 7: Preparation ofN-((1S)-2-((2S,4R)-2-(5,8,11-trioxa-2-azadodecyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide,dihydrochloride salt

A solution ofN-((1S)-2-((2S,4R)-2-(5,8,11-trioxa-2-azadodecyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide(1 equiv) in dichloromethane is reacted with 4M HCl in IPA (5 equiv).After completion of the reaction, the mixture is concentrated undervacuum to affordN-((1S)-2-((2S,4R)-2-(5,8,11-trioxa-2-azadodecyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-1-yl)-1-phenylethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide,dihydrochloride salt.

Example 36 (Prophetic) Preparation ofN—((S)-2-((S)-3-(tert-butylamino)pyrrolidin-1-yl)-1-(4-(2-hydroxyethoxy)phenyl)ethyl)-2-(3,4-dichlorophenyl)-N-methylacetamide

To a solution of(R)-1-((S)-2-(2-(3,4-dichlorophenyl)-N-methylacetamido)-2-(4-(2-hydroxyethoxy)phenyl)ethyl)pyrrolidin-3-ylmethanesulfonate (0.5 g, 0.92 mmol) (preparation described in Step 5 ofExample 25) in acetonitrile (10 mL) is added 2-methylpropan-2-amine(0.08 g, 1.1 mmol) and potassium carbonate (0.153 g, 1.11 mmol). Themixture is heated to 70° C. for four hours. Dichloromethane (100 mL) isadded into the mixture and resultant solution is washed with water anddried over sodium sulfate. The residue is purified by columnchromatography. Using conventional techniques, a salt form of thecompounds is made.

Example 37 (Prophetic) Preparation of2-(3,4-dichlorophenyl)-N—((S)-1-(4-(2-hydroxyethoxy)phenyl)-2-((S)-3-(methylamino)pyrrolidin-1-yl)ethyl)-N-methylacetamide

Using a synthetic approach similar to the one employed in Example 35.The compound2-(3,4-dichlorophenyl)-N—((S)-1-(4-(2-hydroxyethoxy)phenyl)-2-((S)-3-(methylamino)pyrrolidin-1-yl)ethyl)-N-methylacetamideis prepared. Using conventional techniques, a salt form of the compoundsis made.

Example 38 (Prophetic) Preparation of2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-(dimethylamino)pyrrolidin-1-yl)-1-(4-(2-hydroxyethoxy)phenyl)ethyl)-N-methylacetamide

Using a synthetic approach similar to the one employed in Example 35,2-(3,4-dichlorophenyl)-N—((S)-2-((S)-3-(dimethylamino)pyrrolidin-1-yl)-1-(4-(2-hydroxyethoxy)phenyl)ethyl)-N-methylacetamideis prepared. Using conventional techniques, a salt form of the compoundsis made.

It is understood that each of Examples 1-38 described above may bemodified to introduce oligomers of various lengths for each compound, asdisclosed herein.

Example 39 Biology Data of Selected Compounds

Selected compounds were assayed for various biological properties.

The binding affinities of certain compounds of the present inventionwere evaluated using radioligand binding assays in membranes preparedfrom CHO-K1 cells expressing recombinant human kappa (KOR) or mu (MOR)opioid receptors.

Competitive Binding a KOR and MOR: Competition binding experiments wereconducted by incubating membrane protein to equilibrium in triplicate inthe presence of a fixed concentration of radioligand and increasingconcentrations of test compound for evaluation of binding to KOR orsingle concentration (10 μM) of test compound for evaluation of bindingto MOR in 101 μL final volume. The radioligands used were specific foreach receptor type, and the assay conditions are described in Table 1.Following incubations, the membranes were rapidly filtered through GF/Bfilter plate (presoaked with 0.5% polyethyleneimine), washed five timeswith cold 50 mM Tris-HCl, pH 7.5, and the bound radioactivity was thenmeasured by liquid scintillation counting. Non-specific binding wasmeasured in the presence of excess ligand; this value was subtractedfrom the total binding to yield the specific binding at each testconcentration. Assay conditions are reported in Table 1 below.

TABLE 1 Non- Receptor Membrane specific Receptor Source ProteinRadioligand K_(d) binding Methods Kappa Human 2.5 μg/well [³H] 0.3 nMU-50488 Reaction in 50 mM Tris-HCl Opioid recombinant in Diprenorphine(10 μM) (pH 7.5), 5 mM MgCl₂, 0.05% CHO-K1 cells (1 nM) BSA at roomtemperature for 1 h with shaking Mu Human   5 μg/well [³H] Naloxone —Naloxone Reaction in 50 mM Tris-HCl Opioid recombinant in (4 nM) (10 μM)(pH 7.5), 5 mM MgCl₂ at room CHO-K1 cells temperature for 1 h withshaking

For KOR binding, IC₅₀ (concentration of test compound required toinhibit 50% of specific binding) values were obtained from non-linearregression analysis of dose-response curves, using GraphPad's Prism 5.01software, and were calculated for those compounds that showed >50%inhibition of specific binding at the highest concentration tested.K_(i) (affinity of test compound) was obtained using the Cheng Prusoffcorrection using experimental K_(d) (affinity of radioligand) valuesthat were previously determined under these assay conditions. For MORbinding, compounds were tested at one concentration, 10 μM, to evaluateits ability to inhibit specific radioligand binding. The values areexpressed as percent inhibition of specific binding and greater than 50%inhibition of binding was considered to be significant.

Inhibition of cAMP Accumulation:

Inhibition of cAMP accumulation by select compounds was measured inforskolin-stimulated CHO-K1 cells stably expressing KOR. CHO-K1 cellsstably expressing KOR were harvested using Invitrogen Cell DissociationBuffer, and then centrifuged at 1200 rpm for five minutes. Thesupernatant was aspirated and cells were resuspended in assay buffer toa density of 4×10⁵ cells/mL. 25 μL of cells were added into a whitehalf-area 96 well plate. Fourteen point serial dilutions of testcompounds were carried out in assay buffer (PBS with 0.5 mM IBMX).Dynorphin A or U62066 was used as a positive control for each assay.Compound (12.5 μL) was added to the cells in duplicate for each testconcentration. The cells were then stimulated with 12.5 μL forskolin ata final concentration 20 μM. Cells were incubated for 45 minutes in a37° C., 5% CO₂ water jacketed incubator. CisBio HTRF cAMP assay reagentwas used for cAMP quantitation. Two hours after substrate addition,signal at 665/615 nm was measured using the Perkin Elmer Victor X4 HTRFreader. Data analysis was done using GraphPad Prism, sigmoidaldose-response (variable slope) curve fitting.

Data are expressed as means of one experiment in triplicatedetermination and reported in Table 2.

TABLE 2 Binding Activities and Inhibition of cAMP Accumulation ofSelected Compounds Mu Opioid Receptor Mu Receptor Kappa Opioid ReceptorInhibition Compound No. IC50 Ki EC50 cAMP % inhib @ (Example No.) (nM)(nM) (nM) 10 uM 1 37.1 4.84 2 89 2 5.36 0.7 0.311 87.1 3 2.79 0.36 0.2994.2 4 49.71 6.48 1.75 91.8 5 7.74 1.01 1.35 97 6 3.01 0.39 1.15 84.6 70.67 0.09 0.19 99.9 8 0.35 0.05 0.06 99 9 3.58 0.47 0.5 101.2 10 9.611.25 3.74 95.9 11 344.9 44.99 28.8 57.6 12 374.2 48.81 18.46 47.0 130.75 0.10 0.067 95.4 15 5.27 0.69 0.164 23.5 16 10.25 1.34 0.294 28.4 18135.2 17.64 4.67 −3.2 20 57410 7488 2673 −29.4 21 1449 189 33.26 0.0 22247.2 32.25 15.5 −10.3 23 1081 141 53.6 −2 24 20.81 2.71 0.78 40.1

What is claimed is:
 1. A compound having a structure encompassed by thefollowing formula:

wherein R¹ is selected from the group consisting of:

˜N(CH₃)CH₂CH₂OCH₃; ˜CH₂CH(CH₃)OH; ˜N(CH₂CH₂OCH₃)₂; and

and pharmaceutically acceptable salts and solvates of each of theforegoing.
 2. A compound having a structure encompassed by the followingformula:

wherein R² is selected from the group consisting of: ˜CH₂OCH₂CF₃; and˜CH(CH₃)OH, and pharmaceutically acceptable salts and solvates of eachof the foregoing.
 3. A compound having a structure encompassed by thefollowing formula:

wherein R³ is selected from the group consisting of:

and pharmaceutically acceptable salts and solvates of each of theforegoing.
 4. A compound having a structure encompassed by the followingformula:

wherein: G is selected from the group consisting of ˜C(O)˜ and ˜S(O)₂˜;(a) is selected from 0, 1, 2, 3 and 4; R⁴ is selected from the groupconsisting of:

and J is ˜H or ˜CF₃, and pharmaceutically acceptable salts and solvatesof each of the foregoing, with the provisio that the compound is not


5. A compound having a structure encompassed by the following formula:

wherein: (b) is either 0 or 1; and R⁵ is selected from the groupconsisting of:

˜NHCH₂CH₂OCH₂CH₂OCH₂CH₂OCF₃; ˜NHC(CH₃)₃; ˜NHCH₃; and ˜N(CH₃)₂;

and pharmaceutically acceptable salts and solvates of each of theforegoing.
 6. A compound selected from the group consisting of:

and pharmaceutically acceptable salts and solvates of each of theforegoing.
 7. A pharmaceutical composition comprising a compound of anyone of the preceeding claims and at least one pharmaceuticallyacceptable excipient.
 8. A composition of matter comprising a compoundof any one of the preceeding claims, wherein the compound is present ina dosage form.
 9. A method comprising administering a compound of anyone of the preceeding claims to a patient in need thereof.